KR20010005646A - Novel Pyridine Derivatives and Pharmaceutical Compositions Containing Them - Google Patents

Abstract

(I)

A compound of formula (I) wherein X is O or S; R ¹ and R ² are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or R ¹ and R ² are the carbon to which they are attached Together with the atoms form a C _3-6 cycloalkyl group; R ³ is hydrogen and R ⁴ is C _1-6 alkyl or C _3-6 cycloalkyl, or R ³ and R ⁴ together with the carbon atom to which they are attached To form a _3-6 cycloalkyl group). The compounds of the present invention show effectiveness in the treatment or prevention of allergic, inflammatory, autoimmune, proliferative and hyperproliferative diseases.

Description

Novel Pyridine Derivatives and Pharmaceutical Compositions Containing Them

The present invention relates to novel pyridine derivatives, their use as medicaments, pharmaceutical preparations containing them and methods for their preparation.

European patent applications EP-A-0 264 114 and EP-A-0 267 439 disclose certain phenylalkylpyridine alkanol derivatives and phenylalkoxypyridine alkanol derivatives, their use as platelet activator (PAF) antagonists.

A series of compounds with different structures are now found to be useful for the regulation of inflammatory conditions. It is therefore a first aspect of the present invention to provide a compound of formula I or a salt or solvate thereof.

(I)

Where

X is O or S;

R ¹ and R ² are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or together, R ¹ and R ² together form a C _3-6 cycloalkyl group through the carbon atom to which they are attached;

R ³ is hydrogen and R ⁴ is C _1-6 alkyl or C _3-6 cycloalkyl, or R ³ and R ⁴ together form a C _3-6 cycloalkyl group through the carbon atom bonded thereto;

Ar ¹ is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl, wherein the four groups of naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl are halo, nitro, Cyano, pyridyl, thiazinyl, C _1-10 alkyl (optionally substituted with one or more fluorine atoms), -Y-OR ⁵ , -Y-NR ⁶ C (O) NR ⁷ -R ⁸ , -OZC (O ) NR ⁷ R ⁸ , -OYC (S) NR ⁷ R ⁸ , -YC (O) NR ⁷ R ⁸ , -Y-SO ₂ NR ⁷ R ⁸ , -Y-NR ⁷ R ⁸ , -Y-OC (O ) NR ⁷ R ⁸ , -YC (S) NR ⁷ R ⁸ , -YC (O) R ⁹ , -Y-OC (O) R ⁹ , -Y-CO ₂ R ⁹ , -Y-NR ¹⁰ C (O ) NR ¹¹ -ZR ¹² , SO ₂ NR ¹⁰ C (O) NR ⁷ R ⁸ , -Y-SO ₂ NHNR ⁷ R ⁸ , -YC (O) NR ¹¹ -ZR ¹² , -YC (S) NR ¹¹ -ZR Optionally substituted with one or more groups selected from ¹² , -YN (R ¹⁰ ) SO ₂ R ¹¹ , -YN (R ¹⁰ ) C (O) R ^11, or -YN (R ¹⁰ ) CO ₂ R ¹¹ ,

_Wherein Y is one bond, C _1-6 alkylene or C _2-6 alkenylene; R ⁷ and R ⁸ are independently hydrogen or C _1-6 alkyl, or form a 5- to 7-membered heterocyclic ring which is optionally substituted together via a nitrogen atom bonded to these heterocyclic rings, Optionally further contains a heteroatom selected from nitrogen, oxygen or sulfur; R ⁵ , R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ are independently hydrogen or C _1-10 alkyl optionally substituted with one or more fluorine atoms;

Z is C _1-6 alkylene;

R ¹² is NR ¹⁰ C (O) R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , OR ⁵ , NR ⁷ R ⁸ or CO ₂ R ¹³ , where R ⁵ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are As defined above and R ¹³ is hydrogen, C _1-6 alkyl, C _1-6 alkylaryl or aryl and is optionally substituted with a hydroxy group.).

Alkyl, alkylene, alkenyl and alkenylene groups may be linear or branched, whether independent or as part of another group.

Suitably X is O or S, preferably X is O.

Suitably, R ¹ and R ² are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or R ¹ and R ² are spiro linked together through a carbon atom bonded to them To form a C _3-6 cycloalkyl group. Preferably both R ¹ and R ² are hydrogen.

Suitably R ³ is hydrogen and R ⁴ is C _1-6 alkyl or C _3-6 cycloalkyl or together R ³ and R ⁴ together form a C _3-6 cycloalkyl group through the carbon atom to which they are attached . Preferably R ³ is hydrogen and R ⁴ is C _1-6 alkyl, in particular methyl, ethyl or isopropyl, or together R ³ and R ⁴ together form a cyclopropyl group via a carbon atom bonded thereto.

Suitably Ar ¹ is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl, wherein the four groups of naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl are Halo, nitro, cyano, pyridyl, thiazinyl, C _1-10 alkyl (optionally substituted with one or more fluorine atoms), -Y-OR ⁵ , -Y-NR ⁶ C (O) NR ⁷ -R ⁸ , -OZC (O) NR ⁷ R ⁸ , -OYC (S) NR ⁷ R ⁸ , -YC (O) NR ⁷ R ⁸ , -Y-SO ₂ NR ⁷ R ⁸ , -Y-NR ⁷ R ⁸ , -Y -OC (O) NR ⁷ R ⁸ , -YC (S) NR ⁷ R ⁸ , -YC (O) R ⁹ , -Y-OC (O) R ⁹ , -Y-CO ₂ R ⁹ , -Y-NR ¹⁰ C (O) NR ¹¹ -ZR ¹² , SO ₂ NR ¹⁰ C (O) NR ⁷ R ⁸ , -Y-SO ₂ NHNR ⁷ R ⁸ , -YC (O) NR ¹¹ -ZR ¹² , -YC (S) Optionally substituted with one or more groups selected from: NR ¹¹ -ZR ¹² , -YN (R ¹⁰ ) SO ₂ R ¹¹ , -YN (R ¹⁰ ) C (O) R ^11, or -YN (R ¹⁰ ) CO ₂ R ¹¹ Wherein Y is one bond, C _1-6 alkylene or C _2-6 alkenylene. One or more substituents may be present in the Ar ¹ group and plural substituents may be the same or different. Preferably Ar ¹ is a naphthyl or biphenyl group. Preferred substituents of the Ar ¹ group include the groups exemplified in the text.

More preferably Ar ¹ is biphenyl optionally substituted with one or more substituents selected from halo, cyano, alkyl or SO ₂ NR ⁷ R ⁸ . Most preferably Ar ¹ is biphenyl substituted with cyano, halo, methyl or —SO ₂ NH ₂ .

Particularly preferred compounds of the present invention include salts or solvates thereof in addition to those of the free base type exemplified herein.

The compounds of the present invention may form pharmaceutically acceptable solvates or salts. Compounds of formula (I) are added with conventional pharmaceutically acceptable acids (e.g. maleic acid, hydrochloric acid, bromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, oxalic acid, mandelic acid, tartaric acid and methanesulfonic acid) Acid addition salts can be formed. The compounds of the present invention may also form alkali metal salts such as magnesium, sodium, potassium and calcium salts.

Certain compounds of formula (I) may exist in geometric isomeric forms, including enantiomers, and the invention also includes each of these geometric isomeric forms, and mixtures thereof, including racemates. Different geometrical isomeric forms may be separated by conventional methods or specific isomers may be obtained by stereospecific or asymmetric synthesis. The invention also includes any tautomeric forms and mixtures thereof.

The invention also provides a process for the preparation of the compound of formula (I) which comprises the following steps.

(a) reducing the compound of formula II; or

(II)

(Wherein R ³ , R ⁴ , X and Ar ¹ are as defined in formula (I).)

(b) reducing the compound of formula III; or

(III)

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and Ar ¹ are as defined in formula (I).)

(c) preparing a compound of formula I wherein Ar ¹ is a substituted biphenyl group by reaction of a compound of formula IV with a compound of formula V:

(IV)

(V)

Wherein X, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula I, R ¹⁵ is an Ar ¹ substituent as defined in Formula I, R ¹⁶ is a suitable hydroxy protecting group, R One of ¹⁷ / R ¹⁸ is triflate or halo and the other is B (OH) ₂ or ZnHal)

Then randomly in any order

Removal of protector

Converting One Compound Of Formula (I) To Another Compound Of Formula (I)

Formation of pharmaceutically acceptable salts or solvates.

Reduction of the compound of formula II is carried out using a conventional method, for example, hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate. Reduction of the compound of formula III is carried out using conventional methods such as sodium borohydride or zinc borohydride or other reducing agents in a suitable solvent such as ethanol.

(c) The process is, for example, in the presence of a suitable catalyst and base [eg, tetrakis (triphenylphosphine) palladium (O) and aqueous sodium carbonate solution] in a suitable solvent (eg ethanol / toluene). The Suzuki reaction (Synthetic Communications 11 (7), 513-519, 1081) is carried out at 100 ° C.

Compounds of formula (II) can be prepared by oxidation of compounds of formula (VI) and reacting the resulting aldehydes with compounds of formula (VII).

(VI)

Wherein X, Ar ¹ , R ³ and R ⁴ are as defined in formula (I).

(VII)

(Wherein M is lithium, sodium, potassium, MgX 'or ZnX', where X 'is a halogen, optionally with an additive such as boron trifluoride).

Oxidation of the compound of formula VI may be carried out under conventional conditions, for example by Swern oxidation.

The compound of formula VI may be prepared by reduction of the compound of formula VIII with a suitable reducing agent such as lithium aluminum hydride or diborane.

(VIII)

(Wherein X, Ar ¹ , R ³ and R ⁴ are as defined in formula VI and R ¹⁹ is hydrogen, C _1-6 alkyl or benzyl.)

The compound of formula VIII may be prepared by reacting a compound of formula IX with a compound of formula X.

(IX)

(Wherein R ¹⁹ , R ³ and R ⁴ are as defined in formula VIII, and L is a group that can be activated to act as a leaving group such as halogen or a later leaving group such as for example hydroxy.)

Ar ¹ -OH (X)

Wherein Ar ¹ is as defined in formula (I).

This reaction is carried out in the presence of a base such as potassium carbonate or cesium carbonate in an inert solvent such as dimethylformamide or acetone.

Formula VIII compounds may also be prepared using Mitsonobu chemistry using a compound of Formula IX, where L is hydroxy.

Formula IX compounds are commercially available or may be prepared by standard methods. For example, compounds of formula (IX) in which L is hydroxy can be prepared by diazotization of commercially available amino acids. Certain compounds of formula (IX) wherein R ¹⁹ is hydrogen or C _1-6 alkyl, one of R ³ / R ⁴ is hydrogen and the other is methyl are commercially available as lactic acid or esters thereof.

Compounds of formula IV are prepared by reacting a compound of formula XI with a compound of formula XII.

(XI)

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ¹⁶ are as defined above).

(XII)

Wherein R ¹⁷ is triflate or halogen.

The reaction is carried out under conditions of a Mitsonobu reaction, for example in the presence of diethylazodicarboxylate and triphenylphosphine, at about 0-25 ° C., in a suitable solvent (eg toluene). do.

Compounds of formula (XI) can be prepared, for example, by reduction of compounds of formula (VIII) using conventional methods such as hydrogenation with a palladium catalyst in an inert solvent such as ethyl acetate, followed by 'Protective Groups in Organic Synthesis' 2nd Edition, T.W. Greene & P.G.M. Wuts, Wiley-Interscience (1991)] can be prepared by debenzylation using conventional methods.

(XIII)

Compounds of formula (XIII) are described in Reetz et al. Angew. Chem. Suppl., (1983), 1511, can be prepared by reacting a compound of formula (XIV) with a compound of formula (VII).

(XIV)

Wherein R ³ and R ⁴ are as defined in formula (I)

Compounds of formula I can be converted to another compound of formula I using standard methods. For example, chemical hekkeu (Heck chemistry) for use, Ar ¹ group is a compound of Formula I is a substituted bromo is reacted with a compound of formula XV to Ar ¹ groups are -CH = CH = R ²⁰ (wherein Y is CH = CH and R ²⁰ are NR ⁶ C (O) NR ⁷ -R ⁸ , -C (O) NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C (O) OR ⁹ , -NR ¹⁰ C (O) NR ¹¹ -ZR ¹² , or -C (O) NR ¹¹ -ZR ¹² , provided that R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined in Formula I) Can be converted to the compound of I.

H ₂ C = CH-R ²⁰ (XV)

(Wherein R ²⁰ is as defined above)

For example, a compound of formula (I) wherein Ar ¹ is naphthyl substituted with bromo or iodo may be treated with a palladium catalyst and a compound of formula XV in a suitable solvent at elevated temperature. If desired, a palladium catalyst can be formed in the reactor.

By reducing a double bond of a compound of the formula I prepared by the above reaction is, -CH = CH-R ²⁰ group can be converted into further compounds of formula (I). This can be done, for example, under standard hydrogenation conditions with palladium on activated carbon.

Other methods of converting a compound of Formula (I) to additional compounds of Formula (I) will be apparent to those skilled in the art. For example, a compound of formula (I) containing a -YC (O) OR ⁹ group, wherein R ¹ is methyl, is converted to a compound of formula (I) having a -YC (O) NHMe group by treatment with methylamine in methanol at elevated temperature Can be. Preferably this reaction is carried out at about 100 ° C. in a closed vessel. The same conversion can be performed using trimethylaluminum and methylamine hydrochloride in toluene at reduced temperatures, for example about 0 ° C.

Also compounds of formula (I) containing a -YC (O) OR ⁹ group can be converted to the corresponding carboxylic acid by hydrolysis. Preferred conditions include treatment with lithium hydroxide in a suitable solvent system such as, for example, water / THF at ambient temperature.

Compounds of formula (I) containing a -YC (O) OH group can be converted to compounds of formula (I) comprising a -YC (O) NR ⁷ R ⁸ group by reaction with a suitable amine. For example, the amines of formula HNR ⁷ R ⁸ can be reacted in a suitable solvent such as DMF in the presence of 1-hydroxybenzotriazole and 1-ethyl-3- (3'dimethylaminopropyl) -carbodiimide. .

Compounds of formula (I) comprising a -YC (O) NR ⁷ R ⁸ group can be converted to compounds of formula (I) having a -Y-NR ⁷ R ⁸ group by treatment with a borane-tetrahydrofuran complex.

Another synthesis of the compound of formula II is (a) via selective reduction of the compound of formula XVI. Suitable reducing agents include sodium borohydride or zinc borohydride (Tetrahedron Lett., (1985), 26, 4463) and the like.

(XVI)

Wherein R ³ , R ⁴ , X and Ar ¹ are as defined in formula (I)

Triple bonds of compounds of formula XVI may also be reduced using conventional methods such as hydrogenation with a palladium catalyst in an inert solvent such as ethyl acetate to form compounds of formula III.

Compounds of formula (XII) may be prepared by reacting compounds of formula (VIII) as defined above with compounds of formula (VII) as defined below.

The intermediate compounds described above are prepared as described above and are commercially available or may be prepared conventionally using known techniques. Some intermediate compounds are novel and represent additional aspects of the present invention.

It will be appreciated by those skilled in the art that in the above method the functional groups of the intermediate compounds also need to be protected with protecting groups.

Functional groups which are desired to be protected are hydroxy, amino and carboxylic acids and the like. Suitable protecting groups for hydroxy include organosilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl and the like. Suitable protecting groups for amino include tert-butoxycarbonyl or benzyloxycarbonyl and the like. Suitable protecting groups for carboxylic acids include C _1-6 alkyl esters or benzyl esters and the like. Protection and deprotection of functional groups may occur before or after the reaction step.

The use of protecting groups has been described in 'Protective Groups in Organic Chemistry' edited by J. W. F. McOmie, Plenum Press (1973) and in 'Protective Group in Organic Synthesis', 2nd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991).

The compounds of the present invention are useful because they have pharmacological activity, particularly activity in the regulation of inflammatory and allergic states, as shown in the tests described below. The compounds of the present invention interfere with the activation of a range of cell types from the hematopoietic system, including mast cells, neutrophils and eosinophils. Thus in a further aspect of the present invention there is provided a compound of formula (I) and a pharmaceutically acceptable salt or solvate thereof for use in therapy.

Uses of the compounds of the present invention point out their use in the treatment or prevention of allergy, inflammation, autoimmune, proliferative and hyperproliferative diseases.

The compounds of the present invention also include reversible obstructive airway diseases, including asthma (eg, bronchial asthma, allergic asthma, endogenous asthma, exogenous and chronic asthma) and related symptoms of the disease (delayed reaction, hypersensitivity), Farmer's lung and related diseases, fibrosis, edeoptic interstitial pneumonia, chronic obstructive airway disease (COPD), bronchiectasis, cystic fibrosis, eosinophilic pneumonia, adult It has the effect of treating or preventing allergic, inflammatory or autoimmune conditions of the lung, including respiratory distress (ARDS), emphysema and alveolitis (eg idiopathic fibrous alveolitis).

In addition, the compounds of the present invention include acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis (including casein rhinitis, hypertrophic rhinitis, purulent rhinitis and dry rhinitis), drug rhinitis, membranous rhinitis (croup rhinitis, fibrinitis and Allergic, inflammatory or autoimmune of the nose including all conditions characterized by inflammation of the nasal mucosa, such as mucosal rhinitis), adenoid rhinitis, seasonal rhinitis (including neural rhinitis (hay fever)) and vasomotor rhinitis It is also effective in treating and preventing the condition. Of particular interest are allergic rhinitis and series rhinitis (including hay fever). The compounds also show efficacy in the treatment of allergic conditions of nasal polyps and nasopharynx, in addition to those described herein.

The compounds of the present invention may also be used for allergic, inflammatory or autoimmune conditions of the eye, such as conjunctivitis (allergic conjunctivitis, acute conjunctivitis, spring conjunctivitis, conjunctivitis due to hay fever, chronic conjunctivitis), inflammatory diseases of the eyelids, cornea, uveal tract and retina. It is also effective in the treatment and prevention of.

The compounds of the invention are also allergic, inflammatory and autoimmune in the gastrointestinal tract, such as food allergies, food intolerance, ulcerative colitis, Crohn's disease, irritable bowel symptoms, gastric ulcers, and signs far from the gastrointestinal tract. It is also effective in the treatment and prevention of food-related diseases (eg migraine, rhinitis and eczema) that show signs of illness.

The compounds of the present invention are allergic to the skin such as psoriasis, atopic dermatitis, contact dermatitis / herpes dermatitis, nodular erythema, urticaria, dermatitis eosinophilia, acne, alopecia areata, eosinophilic fasciitis dermatitis, irritable light allergy and fascia disease. It is also effective in the treatment and prevention of sexual, inflammatory or autoimmune conditions.

Therefore, the compounds of the present invention are osteoarthritis, rheumatoid arthritis, systemic lupus erythematosis, vasculitis, Wegener's granulomatosis, nodular polyarthritis, bursitis, tendonitis, gout, Behcet's syndrome, It is also effective in the treatment or prevention of allergic, inflammatory or autoimmune conditions of joints and connective tissue, including ankylosing spondylitis, Later syndrome and psoriatic arthritis.

Compounds of the present invention are allergic, inflammatory and autoimmune states of the circulatory system including atherosclerosis, reperfusion injury (e.g. angioplasty), myocardial infarction, thrombosis and ischemia or injury due to vascular and tissue damage. It is effective in the treatment and prevention.

The compounds of the present invention are effective in the treatment and prevention of allergic, inflammatory and autoimmune conditions of the central nervous system (CNS), including Parkinson's disease, Alzheimer's and other dementia, seizures and subarachnoid hemorrhagic conditions. The compounds of the present invention are effective in the treatment and prevention of inflammatory conditions in the liver, for example, hepatitis, cirrhosis and glomerulonephritis.

The compounds of the present invention have an effect on the treatment and prevention of allergic, inflammatory or autoimmune conditions of the bladder and urogenital tract, including cystitis.

The compounds of the present invention have an effect on the treatment and prevention of tumors and other proliferative diseases.

Most interesting of these effects is the use of the compounds of the invention in the treatment and prevention of reversible obstructive airway diseases, in particular asthma and asthmatic rhinitis.

According to a further aspect of the invention, the use of the preparation of a medicament for the treatment and prophylaxis of said diseases, in particular reversible obstructive airway diseases, in particular asthma, of the compounds of formula I or their pharmaceutically acceptable salts or solvates To be used.

Administration of the compounds of the invention may be local (eg inhalation to the lungs). The compounds of the present invention may also be inhaled as dry powders, which may be compressed or uncompressed.

In uncompressed powder compositions, the finely divided form of the active ingredient can be used in admixture with a larger size pharmaceutically acceptable inert carrier.

The composition may optionally be compressed and contain compressed gas (eg nitrogen) or liquefied gas propellant. In such compressed compositions the active ingredient is preferably finely ground. This compression composition may also contain a surface active agent. This compression composition can also be prepared by conventional methods. The compounds of the invention may also be administered systematically (eg oral administration to the gastrointestinal tract). The active ingredient may be formulated using conventional techniques with known auxiliaries, diluents or carriers to produce tablets or capsules for oral administration of the gastrointestinal tract.

Examples of adjuvants, diluents or carriers suitable for oral use in the form of tablets, capsules and dragees include sugars such as microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and And / or gelatin.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof as defined herein together with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable dosages for such oral administration are 0.3 to 30 mg / kg / day (eg 3 mg / kg / day).

According to a further aspect of the present invention, a reversible obstructive airway comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable derivative thereof as defined herein to a patient suffering from disease Methods of treating and preventing diseases, particularly asthma, are provided.

The invention is illustrated by the following examples.

Example 1

(3R, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol and (3S, 4R) -4- (biphenyl-4-yloxy)- 1-pyridin-3-yl-pentan-3-ol

a) (2R) -2- (biphenyl-4-yloxy) propionic acid, ethyl ester

Diethylazodicarboxylate (8.66 ml) in anhydrous tetrahydrofuran (25 ml) was treated with trifetylphosphine (13.11 g), (S)-(-)-ethyl lactate (5.67 ml) and 4-phenylphenol ( 8.51 g) was added dropwise to the stirred solution in anhydrous tetrahydrofuran (100 ml) over 30 minutes. The resulting solution was stirred at rt for 18 h and then concentrated under reduced pressure. A mixture of isohexane: ether (9: 1) (200 ml) was added to the residue and stirred for 30 minutes at room temperature. This solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with isohexane: dichloromethane (2: 3) to give a sub-title compound as an oil (11.79 g).

¹ H NMR (CDCl ₃ ) 7.55-7.47 (4H, m); 7.43-7.38 (2H, m); 7.32-7.25 (1 H, m); 6.97-6.92 (2H, m); 4.78 (1 H, q); 4.24 (2H, q); 1.64 (3 H, d); 1.26 (3 H, t).

b) (2R) -2- (biphenyl-4-yloxy) propan-1-ol

Lithium aluminum hydride (86.67 ml, 1.0 M solution in tetrahydrofuran) (2R) -2- (biphenyl-4-yloxy) propanoic acid, ethyl ester in anhydrous tetrahydrofuran (200 ml) at 0 ° C. (11.79 g, Example 1a) was added dropwise. The resulting solution was stirred at room temperature under nitrogen for 3 hours. Water (3.3 ml) followed by aqueous sodium hydroxide solution (50% solution, 3.3 ml), followed by water (9.9 ml) was carefully added to this solution at 0 ° C. Diethyl ether (200 ml) and anhydrous magnesium sulfate (20 g) were added and the solution was stirred at room temperature for 20 minutes. The solution was filtered and the filtrate was concentrated under reduced pressure to give a subtitle compound as a solid (9.43 g).

m.p. 76-77.6 ℃

MS (EI) 228 (M) ⁺

¹ H NMR (CDCl ₃ ) 7.56-7.49 (4H, m); 7.39 (2H, t); 7.33-7. 28 (1 H, m); 7.03-6.98 (2H, m); 4.57-4.52 (1 H, m); 3.83-3.69 (2H, m); 2.02 (1H, doublet of single); 1.31 (3 H, d).

The subtitle compound may also be prepared as follows.

Suspension of 4-biphenol (3.4 g), (S)-(+)-2-bromopropionic acid (3.06 g) and potassium carbonate (5.52 g) in acetone (50 ml) was heated at reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was partitioned between water (100 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml) and ether (100 ml). The organic layer was separated and the aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The remaining white solid was immediately dissolved in tetrahydrofuran (50 ml) and cooled to 0 ° C. A solution of lithium aluminum hydride (1M solution in diethyl ether, 20 ml) was added dropwise. The reaction solution was left to warm to room temperature, stirred for 1 hour, and then cooled back to 0 ° C. Water (0.75 ml), sodium hydroxide solution (50% w / v, 0.75 ml) and a second small amount of water (2 ml) were carefully added. The resulting mixture was stirred at room temperature for 30 minutes, then dried over anhydrous magnesium sulfate (10 g), filtered and concentrated to give the subtitle compound as a solid (1.44 g).

m.p. 66-69 ℃

MS (APCI) 229 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.56-7.50 (4H, m); 7.42 (2H, t); 7.31 (1 H, t); 7.01 (2H, d); 4.58-4.51 (1 H, m); 3.77-3.71 (2H, m); 2.03 (1H, broad singlet); 1.31 (3 H, d).

c) (2R, 3SR) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pent-4-yn-3-ol

Oxalyl chloride (1.4 ml) was added dropwise to a solution of dimethyl sulfoxide (1.70 ml) in anhydrous dichloromethane (60 ml) at -60 ° C. The resulting solution was stirred for 20 minutes, and then (2R) -2- (biphenyl-4-yloxy) -1-propanol (2.88 g, Example 1b) in anhydrous dichloromethane (20 ml) was added dropwise. The mixture was further stirred for 30 minutes and then triethylamine (11.2 ml) was added dropwise. The mixture was allowed to reach room temperature with stirring for over 1 hour. The mixture was diluted with anhydrous ether (100 ml), filtered and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (20 ml) and 3-pyridylacetylene (1.04 g) in 1-rithio-2-pyridin-3-ylacetylene [tetrahydrofuran (40 ml) (J. Amer. Chem Soc. 1935,57,1284) solution was added by stirring with n-butyllithium (2.5M in hexane, 4.4 ml) for 20 minutes. The mixture was stirred at -60 [deg.] C. for 1 hour and allowed to warm to room temperature for over 2 hours. The mixture was poured into saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with ethyl acetate: hexanes (1: 4) followed by ethyl acetate to give a subtitle compound which was a solid as a 4: 1 mixture of diastereomers (2.18 g).

MS (APCI) 330 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.72 (1H, dd); 8.55 (1 H, doublet of double); 7.76-7. 72 (1 H, m); 7.55-7.52 (4H, m); 7.44 (2H, t); 7.34-7. 26 (2H, m); 7.07-7.04 (2H, m); 4.86-4.83 (1 H, m); 4.67-4.64 (1 H, m); 2.78 (1 H, d); 1.51 (3H, d).

d) (2R, 3RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pentan-3-ol

(2R, 3RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pent-4-yn-3-ol (4.86 g, Example 1c) in ethyl acetate (100 ml) It was dissolved and hydrogenated using 10% palladium on activated carbon (5 g) at 5 atm as a catalyst. Celite this mixture Filtration through and the filtrate was concentrated under reduced pressure to give the title compound (3.95 g).

This diastereomer is separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:20) to afford the title compound.

Product (3R, 4R) was recrystallized from ethyl acetate: isohexane (1: 4) to give (3R, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentane-3 -Ol was obtained as a solid (0.25 g).

m.p. 98-99.5 ℃

MS (APCI) 334 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.50 (5H, m); 7.41 (2H, t); 7.33-7. 31 (1 H, m); 7.24-7. 21 (1 H, m); 6.97 (2H, d); 4.28 (1H, quintet); 3.68-3.64 (1 H, m); 2.96-2.89 (1 H, m); 2.83-2.76 (1 H, m); 2.51 (1 H, d); 1.90-1.83 (2H, m); 1.29 (3 H, d).

(3S, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) was recrystallized from ethyl acetate: isohexane (1: 1) Trituration afforded the title compound as a solid (2.23 g).

m.p. 121.5-123 ℃

MS (APCI) 334 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.49 (5H, m); 7.42 (2H, t); 7.39-7. 33 (1 H, m); 7.26-7. 22 (1 H, m); 6.94 (2H, d); 4.40-4.37 (1 H, m); 3.89-3.85 (1 H, m); 3.0-2.95 (1 H, m); 2.76-2.71 (1 H, m); 2.28 (1 H, d); 1.89-1.81 (2H, m); 1.31 (3 H, d).

Example 2

(3R, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol and (3S, 4S) -4- (biphenyl-4-yloxy)- 1-pyridin-3-yl-pentan-3-ol

a) (2S) -2- (biphenyl-4-yloxy) propionic acid, ethyl ester

Anhydrous tetrahydrofuran of diethylazodicarboxylate (6.74 ml), triphenylphosphine (13.11 g), (R)-(+)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) Prepared according to the method described in Example 1a from a solution in (125 ml). The residue obtained after completion of the reaction was purified by silica column chromatography eluting with isohexane: dichloromethane (2: 3) to give a subtitle compound as an oil (11.3 g).

MS (EI) 270 (M) ⁺

¹ H NMR (CDCl ₃ ) 7.55-7.47 (4H, m); 7.43-7.38 (2H, m); 7.32-7.25 (1 H, m); 6.97-6.92 (2H, m); 4.78 (1 H, q); 4.24 (2H, q); 1.64 (3 H, d); 1.26 (3 H, t).

b) (2S) -2- (biphenyl-4-yloxy) propan-1-ol

(2S) -2- (biphenyl-4-yloxy) propanoic acid, ethyl ester (11.3) in lithium aluminum hydride (41.9 ml, 1.0 M solution in ether) and anhydrous tetrahydrofuran (200 ml) at 0 ° C. g, Example 2a) Prepared from the solution according to the method described in Example 1b. The subtitle compound obtained after the completion of the reaction was used directly (9.52 g) without further purification.

m.p. 75-78 ℃

MS (EI) 228 (M) ⁺

¹ H NMR (CDCl ₃ ) 7.56-7.49 (4H, m); 7.39 (2H, t); 7.33-7. 28 (1 H, m); 7.03-6.98 (2H, m); 4.57-4.52 (1 H, m); 3.83-3.69 (2H, m); 2.04-1.99 (1H, doublet); 1.31 (3 H, d).

c) (3RS, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pent-4-yn-3-ol

(2S) -2- (biphenyl-4-yloxy) -1-propanol (2.88 g, Example 2b), oxalyl chloride (1.4 ml), dimethyl sulfoxide (1.70 ml), triethylamine (11.18 ml), 3-pyridylacetylene (1.04 g) and n-butyllithium (2.5 M in hexane, 4.4 ml), according to the method described in Example 1c, as a cream solid as a 4: 1 mixture of diastereomers A phosphorus subtitle compound was obtained (2.13 g).

MS (APCI) 330 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.72 (1H, dd); 8.55 (1 H, doublet of double); 7.76-7. 72 (1 H, m); 7.55-7.52 (4H, m); 7.44 (2H, t); 7.34-7. 26 (2H, m); 7.07-7.04 (2H, m); 4.86-4.83 (1 H, m); 4.67-4.64 (1 H, m); 2.78 (1 H, d); 1.51 (3H, d).

d) (3RS, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

In (2S, 3RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pent-4-yn-3-ol (4.16 g, Example 4c), ethyl acetate (100 ml) Prepared according to the method described in Example 1d from 10% palladium on activated carbon (0.5 g) to give a subtitle compound which was a white solid as a 4: 1 mixture of diastereomers (4.13 g).

This diastereomer is separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:20) to afford the title compound.

Recrystallize (3S, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (subdiastereomer) from ethyl acetate: isohexane (1: 4) Trituration afforded the title compound as a solid (0.352 g).

m.p. 102.5-103.5 ℃

MS (APCI) 334 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.50 (5H, m); 7.41 (2H, t); 7.33-7. 31 (1 H, m); 7.24-7. 21 (1 H, m); 6.97 (2H, d); 4.28 (1H, quintet); 3.68-3.64 (1 H, m); 2.96-2.89 (1 H, m); 2.83-2.76 (1 H, m); 2.52 (1 H, d); 1.90-1.83 (2H, m); 1.29 (3 H, d).

(3R, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) was recrystallized from ethyl acetate: isohexane (1: 1) Trituration afforded the title compound as a solid (1.76 g).

m.p. 123.5-124 ℃

MS (APCI) 334 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.49 (5H, m); 7.42 (2H, t); 7.39-7. 33 (1 H, m); 7.26-7. 22 (1 H, m); 6.94 (2H, d); 4.40-4.37 (1 H, m); 3.89-3.85 (1 H, m); 3.0-2.95 (1 H, m); 2.76-2.71 (1 H, m); 2.24 (1 H, d); 1.89-1.81 (2H, m); 1.31 (3 H, d).

Example 3

Via diastereoisomers

(3R, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

a) (2S) -methoxyphenylacetic acid, 2- (biphenyl-4-yloxy) -1- (2-pyridin-3-ylethyl) propyl ester.

Solid (S)-(+)-α-methoxyphenylacetic acid (0.25 g), 4-dimethylaminopyridine (0.18 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloro Read (0.29 g) to (3RS, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.44 g, Example 2c) anhydrous dichloromethane ( 30 ml). The reaction was stirred at room temperature for 20 hours, and then concentrated under reduced pressure. The residue was purified by silica chromatography eluting with ethyl acetate: hexanes (2: 1) to give a subtitle compound as an oil (0.44 g).

MS (APCI) 482 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.40 (1 H, d); 8.11 (1 H, d); 7.56-7.48 (6H, m); 7.48-7.37 (6H, m); 7.15-7.12 (2H, m); 6.92 (2H, d); 5.18-5.02 (1 H, m); 4.76 (1 H, s); 4.52 (1H, dq); 3.41 (3H, s); 2.22-2.11 (2H, m); 1.97-1.9 (2H, m); 1.30 (3 H, d).

b) (3R, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

Water (1 ml) and lithium hydroxide (0.063 g) were added (S) -α-methoxyphenylacetic acid (2S, 3R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl- Pent-3-yl ester (0.44 g) was added to a solution in methanol (5 ml) and the resulting solution was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate: hexanes (1: 3) to give the title compound as a solid (0.21 g).

m.p. 122-123 ℃

MS (APCI) 334 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, d); 7.57-7.50 (5H, m); 7.43 (2H, t); 7.33 (1 H, t); 7.23 (1 H, doublet of double); 6.97 (2H, d); 4.39 (1 H, qd); 3.88-3.86 (1 H, m); 2.96-2.92 (1 H, m); 2.78-2.72 (1 H, m); 2.05 (1H, broad singlet); 1.89-1.83 (2H, m); 1.31 (3 H, d).

Example 4

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile and (1S, 2S) -4'-(2-hydroxy -1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile

a) (2S) -2- (4-bromophenoxy) propionic acid, ethyl ester

Anhydrous tetrahydro of diethylazodicarboxylate (6.7 ml), triphenylphosphine (13.11 g), (R)-(+)-ethyl lactate (5.67 ml) and 4-bromophenol (8.65 g) Prepared according to the method described in Example 1a from a solution in furan (125 ml). The residue obtained after the reaction was purified by silica column chromatography eluting with isohexane: dichloromethane (2: 3) to give a subtitle compound as an oil (12.2 g).

¹ H NMR (CDCl ₃ ) 7.36 (2H, d); 6.75 (2H, d); 4.69 (1 H, q); 4.20 (2H, q); 1.61 (3 H, d); 1.25 (3 H, t).

b) (2S) -2- (4-bromophenoxy) propan-1-ol

Sodium borohydride (1.15 g) was added to a solution in (2S) -2- (4-bromophenoxy) propionic acid, ethanol (200 ml) of ethyl ester (7.5 g, Example 4a) at 5 ° C. . The resulting solution was allowed to stand at room temperature, stirred for 10 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (50 ml). The mixture was extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. This product was used directly in the next step without further purification (6.32 g).

MS (EI) 230,232 (M) ⁺

¹ H NMR (CDCl ₃ ) 7.39 (2H, d); 6.83 (2H, d); 4.50-4.41 (1 H, m); 3.77-3.70 (2H, m); 1.93 (1 H, broad singlet); 1.26 (3 H, d).

c) (3RS, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pent-1-yn-3-ol

(2S) -2- (4-bromophenoxy) propan-1-ol (9.24 g, Example 4b), oxalyl chloride (4.38 ml), dimethyl sulfoxide (4.4 ml), triethylamine (22.4 ml), 3-pyridylacetylene (6.3 g) and n-butyllithium (2.5 M in hexane, 24 ml), prepared according to the method described in Example 1c, being an oil as a 4: 1 mixture of diastereomers. A subtitle compound was obtained (8.31 g).

MS (APCI) 332,334 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.73 (1H, d); 8.53 (1H, doublet of double); 7.74-7.70 (1 H, m); 7.39 (2H, d); 7.29-7. 24 (1 H, m); 8.67 (2 H, d); 4.82-4.78 (1 H, m); 4.57-4.53 (1 H, m); 3.43 (1 H, broad singlet); 1.45 (3 H, d).

d) (3RS, 4R) -4- (4-Bromophenoxy) -1-pyridin-3-yl-pentan-3-ol

5 on (3RS, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pent-4-yn-3-ol (7.0 g, Example 4c) and activated carbon (1.0 g) Prepared according to the method described in example 1d) from a solution in% rhodium in ethyl acetate (100 ml) to give a subtitle compound which is an oil as a 4: 1 mixture of diastereomers (5.6 g).

MS (APCI) 336,338 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.50 (1H, d); 8.45 (1 H, doublet of doublets); 7.54 (1 H, dt); 7.37 (2H, d); 7.22 (1H, doublet of double); 6.76 (2H, d); 4.30-4.27 (1 H, m); 3.82 (1 H, p); 2.94-2.89 (1 H, m); 2.77-2.70 (1 H, m); 2.18 (1 H, broad singlet); 1.86-1.78 (2H, m); 1.26 (3 H, d).

e) (1R, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile and (1R, 2S) -4'-(2- Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile

(3RS, 4R) -4- (4-Bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (1.0 g, Example 4d), 3-cyanobenzeneboronic acid (0.74 g), a solution of 2M aqueous solution of sodium carbonate (5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (25 ml) and ethanol (5 ml) was refluxed for 3 hours. The reaction mixture was cooled down, poured into water (100 ml) and extracted with ethyl acetate (3 × 50 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a subtitle compound which was an oil as a 4: 1 mixture of diastereomers (0.86 g).

These diastereoisomers were separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:33) to afford the title compound.

(1S, 2S) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile (subdiastereomer) as an oil (0.22 g).

MS (APCI) 359 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.47 (1 H, d); 7.82 (1 H, s); 7.76 (1 H, dt); 7.60-7.48 (5H, m); 7.25-7.21 (1 H, m); 7.10 (2 H, d); 4.30 (1 H, p); 3.72-3.64 (1 H, m); 2.99-2.90 (1 H, m); 2.84-2.74 (1 H, m); 2.44 (1 H, d); 1.91-1.84 (2H, m); 1.30 (3 H, d).

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile (main diastereomer) (0.52 g) as an oil.

MS (APCI) 359 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.47 (1 H, d); 7.82 (1 H, s); 7.76 (1 H, dt); 7.60-7.48 (5H, m); 7.25-7.21 (1 H, m); 7.10 (2 H, d); 4.42-4.39 (1 H, m); 3.88-3.82 (1 H, m); 3.01-2.90 (1H, m); 2.84-2.74 (1 H, m); 2.20 (1 H, d); 1.88-1.84 (2H, m); 1.32 (3 H, d).

Example 5

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-sulphonic acid amide and (1S, 2S) -4'- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-sulphonic acid amide

a) (3RS, 4S) -3- [4- (4-bromophenoxy) -3- (tertbutyldimethylsilanyloxy) pentyl] pyridine.

Tert- to a solution of (3RS, 4S) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (2.0 g, Example 4d) in anhydrous dichloromethane (50 ml). Butyldimethylsilyl chloride (1.17 g) and imidazole (1.08 g) were added and the resulting solution was stirred for 24 hours and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexanes (1: 4 to 1: 1) to give the subtitle compound as an oil (2.52 g).

MS (APCI) 450.1, 452.1 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.45-8.42 (2H, m); 7.4 (1 H, dt); 7.35 (2H, d); 7.22-7.18 (1 H, m); 6.73 (2H, d); 4.23-4.20 (1 H, m); 3.82-3.78 (1 H, m); 2.84-2.62 (2H, m); 1.96-1.88 (1 H, m); 1.82-1.78 (1 H, m); 1.27 (3 H, d); 0.94 (9H, s); 0.12 (3H, s); 0.09 (3H, s).

b) (1S, 2RS) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid.

A tert-butyllithium (2.5 ml, 1.7 M in hexane) solution was added (2S, 3RS) -2- (4-bromophenoxy) -3-tert-butyldimethylsilyloxy-5-pyridin-3-ylpentane ( 1.60 g, Example 5b) and triisopropylborate (1.07 ml) were added to a solution in tetrahydrofuran (25 ml) at −78 ° C. over a period of 1 hour. The resulting solution was stirred at −78 ° C. for 2 hours, and then the reaction was terminated by addition of saturated aqueous ammonium chloride solution (50 ml). The mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica chromatography eluting with ethyl acetate followed by ethyl acetate: methanol (4: 1) to give the subtitle compound as a foam (1.2 g).

¹ H NMR (CDCl ₃ , major diastereomer) 8.60-8.53 (2H, m); 7.95 (2H, d); 7.6-7.54 (1 H, m); 7.26-7. 22 (1 H, m); 6.86 (2H, d); 4.33-4.27 (1 H, m); 3.93-3.86 (1 H, m); 2.82-2.62 (2H, m); 1.98-1.75 (2H, m); 1.28 (3 H, d); 0.94 (9H, s); 0.08 (6 H, s).

c) (1S, 2R) -4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulphonic acid amide and (1S, 2S) -4' (2- Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulphonic acid amide.

(1S, 2RS) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (1.9 g, Example 5b), 3- Bromobenzenesulfonamide (1.62 g), 2M aqueous sodium carbonate solution (5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in a solution in toluene (25 ml) and ethanol (5 ml) as described in Example 4e. It was prepared according to the method described. The reaction was refluxed for 3 hours. The solvent was concentrated in vacuo and the residue was redissolved in methanol (5 ml) and concentrated hydrochloric acid (1 ml) was added. After 16 hours, the mixture was evaporated again and reaction finished as described in Example 4e to give the subtitle compound as a mixture of diastereomers (1.62 g);

These diastereoisomers were separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:33) to afford the title compound.

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulphonic acid amide (main diastereomer) as a oil (0.70 g).

MS (APCI) 413.1 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.49 (1 H, d); 8.45 (1 H, d); 8.10 (1 H, t); 7.87 (1 H, dt); 7.75 (1 H, dt); 7.58-7.49 (4H, m); 7.49-7.21 (1 H, m); 6.95 (2H, d); 5.03 (2H, s); 4.41-4.37 (1 H, m); 3.83-3.80 (1 H, m); 3.01-2.92 (1 H, m); 2.80-2.71 (1 H, m); 2.32 (1 H, broad singlet); 1.90-1.82 (2H, m); 1.31 (3 H, d).

(1S, 2S) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulphonic acid amide (subdiastereomer) as an oil (0.31 g).

MS (APCI) 413.1 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.46 (1 H, d); 8.10 (1 H, t); 7.87 (1 H, dt); 7.75 (1 H, dt); 7.58-7.49 (4H, m); 7.49-7.21 (1 H, m); 6.99 (2H, d); 4.87 (2H, s); 4.30 (1 H, p); 3.73-3.63 (1 H, m); 3.01-2.92 (1 H, m); 2.80-2.71 (1 H, m); 2.46 (1 H, broad singlet); 1.90-1.82 (2H, m); 1.30 (3 H, d).

Example 6

(3R, 4S) -4- (3'-Chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol oxalic acid salt and (3S, 4S) -4- (3 '-Chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol oxalic acid salt

(3RS, 4R) -4- (4-Brophenoxy) -1-pyridin-3-yl-pentan-3-ol (1.05 g, Example 4d), 3-chlorobenzene boronic acid (1.1 g) , Diastereomer prepared from 2M aqueous solution of sodium carbonate (3.6 ml) and tetrakis (triphenylphosphine) palladium (0) (0.36 g), toluene (25 ml) and ethanol (5 ml) according to the method described in Example 4e A subtitle compound which is an oil as a 4: 1 mixture of isomers was obtained (1.09 g).

The diastereomers are separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:33) to prepare two oils, which are treated with oxalic acid (excess) in ether to convert to oxalate salts. The title compound was obtained.

(3S, 4S) -4- (3'-Chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol oxalic acid salt (subdiastereomer) as a solid (0.11 g ).

m.p. 71-73 ℃

MS (APCI) 368 [(M-oxalic acid) + H] ⁺

¹ H NMR (DMSO-D6) 8.46 (1 H, d); 8.40 (1 H, doublet of double); 7.68-7. 57 (5H, m); 7.45 (1 H, t); 7.37-7.30 (2H, m); 7.0 (2H, d); 4.45-4.37 (1 H, m); 4.0 (1H, broad singlet); 3.58-3.53 (1 H, m); 2.87-2.78 (1 H, m); 2.68-2.58 (1 H, m); 1.81-1.69 (2H, m); 1.21 (3 H, d).

(3R, 4S) -4- (3'-Chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol oxalic acid salt (main diastereomer) as a solid (0.50 g) ).

m.p. 146.5-147.5 ℃

MS (APCI) 368 [(M-oxalic acid) + H] ⁺

¹ H NMR (DMSO-D6) 8.47 (1 H, d); 8.42 (1 H, doublet); 7.70-7.56 (5H, m); 7.44 (1 H, m); 7.36-7.32 (2H, m); 7.0 (2H, d); 4.36-4.32 (1 H, m); 3.58-3.53 (1 H, m); 2.86-2.78 (1 H, m); 2.71-2.64 (1 H, m); 1.89-1.85 (1 H, m); 1.68-1.63 (1 H, m); 1.24 (3 H, d).

Example 7

(3R, 4S) -4- (4'-Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol and (3S, 4R) -4- (4'- Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol.

(3RS, 4R) -4- (4-Bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (1.0 g, Example 4d), 4-fluorobenzeneboronic acid (0.62 g), a 2M aqueous solution of sodium carbonate (2.2 ml) and tetrakis (triphenylphosphine) palladium (0) (0.34 g), toluene (30 ml) and ethanol (10 ml) were prepared according to the method described in Example 4e as a solid. The title compound was obtained as a 4: 1 mixture of diastereomers (0.6 g). This diastereomer is separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:33) to give two solids, which are recrystallized from hexane: ethyl acetate (1: 1) to give the title compound.

(3R, 4S) -4- (4'-Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) (0.26 g) as a solid.

m.p. 121-122 ℃

MS (APCI) 352 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.45 (1 H, doublet of doublets); 7.60-7.55 (1 H, m); 7.50-7.40 (4H, m); 7.25-7.20 (1 H, m); 7.05-7.15 (2H, m); 7.0-6.95 (2H, m); 4.45-4.35 (1 H, m); 3.90-3.80 (1 H, m); 3.0-2.90 (1 H, m); 2.80-2.65 (1 H, m); 2.50 (1 H, d); 1.90-1.80 (2H, m); 1.30 (3 H, d).

(3S, 4S) -4- (4'-fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (subdiastereomer) as a solid (0.106 g).

m.p. 147-148 ℃

MS (APCI) 352 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.45 (1 H, doublet of doublets); 7.60-7.55 (1 H, m); 7.50-7.40 (4H, m); 7.25-7.20 (1 H, m); 7.05-7.15 (2H, m); 7.0-6.95 (2H, m); 4.30-4.20 (1 H, m); 3.70-3.60 (1 H, m); 3.0-2.90 (1 H, m); 2.85-2.70 (1 H, m); 2.45 (1 H, d); 1.90-1.80 (2H, m); 1.30 (3 H, d).

Example 8

(3R, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-hexan-3-ol.

a) (2S) -2- (biphenyl-4-yloxy) -3-methylbutyric acid, methyl ester

Diethylazodicarboxylate (11.5 ml) in anhydrous tetrahydrofuran (40 ml) was diluted with triphenylphosphine (22 g) and methyl (R) -2-hydroxy-3-methylbutanoate (11.2 g, J. Am. Chem. Soc., (1990), 112, 21, 7659) and dropwise addition over 30 minutes to a stirred solution of 4-phenylphenol (14.5 g) in anhydrous tetrahydrofuran (120 ml). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. A mixture of isohexane: ether (9: 1) (750 ml) was added to the residue and the mixture was stirred at room temperature for 30 minutes. This solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with isohexane: dichloromethane (1: 4) followed by (1: 1) to give the subtitle compound as a solid, which was recrystallized from hexane to give a crystallized solid (7.9 g) was obtained.

m.p. 82-85 ℃

¹ H NMR (CDCl ₃ ) 7.55-7.45 (4H, m); 7.41 (2H, t); 7.35-7.25 (1 H, m); 6.94 (2H, dt); 4.42 (1 H, d); 3.77 (3H, s); 2.30 (1 H, sextet); 1.11 (3 H, d); 1.08 (3 H, d).

b) (2S) -2- (biphenyl-4-yloxy) -3-methylbutan-1-ol.

A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 16 ml) was added (2S) -2- (biphenyl-4-yloxy) -3-methylbutyric acid, methyl ester in anhydrous tetrahydrofuran (80 ml). (4.0 g, Example 8a) was added dropwise at room temperature, and the reaction was allowed to stir overnight. Water (0.6 ml), then aqueous sodium hydroxide solution (50%, 0.6 ml), and then water (2.4 ml) were carefully added to this solution at 0 ° C. Diethyl ether (200 ml) and anhydrous magnesium sulfate (10 g) were added and the solution was stirred at room temperature for 10 minutes. This solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane followed by dichloromethane: ether (49: 1) to give an oily subtitle compound which was left to solidify (3.43 g).

m.p. 45-47 ℃

¹ H NMR (CDCl ₃ ) 7.58-7.48 (4H, m); 7.41 (2H, t); 7.35-7.25 (1 H, m); 7.04 (2H, d); 4.25-4.15 (1 H, m); 3.90-3.75 (2H, m); 2.10 (1 H, sextet); 1.77 (1 H, doublet of doublets); 1.1-0.9 (6H, m).

c) (3RS, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-hex-1-yn-3-ol

Oxalyl chloride (1.65 ml) was added dropwise to a solution of dimethyl sulfoxide (2.25 ml) in anhydrous dichloromethane (120 ml) at -65 ° C. The resulting solution was stirred for 10 minutes and then (2S) -2- (biphenyl-4-yloxy) -3-methylbutan-1-ol (3.40 g, Example 8b) in anhydrous dichloromethane (30 ml). The solution was added dropwise at -65 ° C. The mixture was further stirred for 15 minutes, and then triethylamine (12 ml) was added dropwise. This mixed solution was left to warm to 10 ° C while stirring. The mixture was then diluted with isohexane (250 ml), stirred for 10 minutes, filtered and concentrated under reduced pressure. The residue is dissolved in anhydrous tetrahydrofuran (20 ml) and it is dissolved 1-rithio-2-pyridin-3-ylacetylene [n-butyllithium (2.5M in hexane, 8.4 ml) at -20 ° C tetrahydrofuran. To pyridilacetylene (2.0 g) (J. Amer. Chem. Soc. 1935, 57, 1284) in (80 ml) was added to the solution for 20 minutes with stirring at -60 ° C. The mixture was left to warm to room temperature and after 30 minutes it was poured into water (200 ml). The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane: ethyl acetate (4: 1) to give an auxiliary title compound which was an oil as a 3: 1 mixture of diastereomers (4.38 g).

MS (APCI +) 358 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.65 & 8.58 (with 1H, 2 × d); 7.52-7.48 (1 H, m); 7.65-7.46 (5H, m); 7.42 (2H, m); 7.35-7.10 (4H, m); 4.93-4.83 (1 H, m); 4.38-4.30 (1 H, m); 2.75-2.65 (1 H, m); 2.32 (1 H, septet); 1.15-1.05 (6H, m).

d) (3RS, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-3-hexanol

(3RS, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-hex-1-yn-3-ol (4.38 g, Example 8c) was ethyl acetate It was dissolved in (100 ml) and hydrogenated at 3 atmospheres using 10% palladium on activated carbon (0.6 g) as a catalyst. Celite Filtration was carried out through, and the filtrate was concentrated under reduced pressure to give a compound as a subtitle as an oil (4.68 g).

This diastereoisomer was separated by standard phase HPLC eluting with isopropanol: dichloromethane (1:20) to give a subtitle compound as an oil, which was converted to their oxane salts by treatment with a saturated ether solution of oxalic acid.

(3S, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-3-hexanol oxalic acid salt (subdiastereomer).

m.p. 75 ° C (dec.)

MS (APCI +) 362.2 (M-oxalic acid + H) ⁺

¹ H NMR (DMSO) 8.42-8.32 (2H, m); 7.65-7.50 (5H, m); 7.40 (2H, t); 7.35-7.25 (2H, m); 7.08 (2H, m); 4.1-4.05 (1 H, m); 3.7-3.65 (1 H, m); 2.85-2.7 (1 H, m); 2.68-2.55 (1 H, m); 2.08 (1 H, sextet); 1.75-1.65 (2H, m); 1.0-0.85 (6 H, m).

(3R, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-3-hexanol oxalic acid salt (main diastereomer).

m.p. 100-105 ℃

MS (APCI +) 362.2 (M-oxalic acid + H) ⁺

¹ H NMR (DMSO) 8.39 (2H, s); 7.65-7.50 (5H, m); 7.42 (2H, t); 7.35-7.25 (2H, m); 7.05 (2H, d); 4.15-4.10 (1 H, m); 3.7-3.55 (1H, m); 2.85-2.55 (2H, m); 2.20-2.10 (1 H, m); 1.9-1.7 (1 H, m); 1.7-1.55 (1 H, m); 0.94 (3H, d); 0.89 (3H, d).

Example 9

(±) -1- [1- (biphenyl-4-yloxy) -cyclopropyl] -3-pyridin-3-yl-propan-1-ol.

a) 4- (1-phenylsulfanyl-cyclopropoxy) biphenyl.

Butyl lithium (2.5 M in hexane, 6.1 ml) was added to a stirred solution of phenylcyclopropyl sulfide (2 g) in anhydrous tetrahydrofuran (45 ml) at 0 ° C. under nitrogen. Stirring was continued at 0 ° C. for 3 hours, then the solution was cooled to −78 ° C. and iodine (4.05 g) in anhydrous tetrahydrofuran (20 ml) was added at 10 minute intervals. Stirring was continued for 15 minutes at this temperature, then sodium metabissulphite solution (10% aqueous solution, 20 ml) was added and the mixture was allowed to warm to room temperature. The iodinated product was extracted with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a light brown oil.

The oil was dissolved in acetonitrile (30 ml) and 4-biphenol (2.7 g) and cesium carbonate (5.2 g) were added. This mixture was heated at reflux for 24 hours. The cooled mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane: hexane (1:19) to give an oily subtitle compound (0.95 g).

MS (EI) 318 (M) ⁺

¹ H NMR (DMSO) 7.70-7.60 (4H, m); 7.53-7.27 (8H, m); 7.18 (2H, d); 1.55-1.38 (4H, m).

b) (±) -1- [1- (biphenyl-4-yloxy) -cyclopropyl] -3-pyridin-3-yl-propan-1-ol.

Lithium naphthalenide (0.625M, 7.4ml; prepared by adding the same mole of naphthalene and lithium metal to tetrahydrofuran under nitrogen and stirring at room temperature overnight) was added 4- (1-phenylsulphur) at -78 ° C under nitrogen. Panylcyclopropoxy) biphenyl (0.7 g) was added slowly to a stirred solution in anhydrous tetrahydrofuran and stirred at this temperature for 15 minutes. To this was added a solution of 3-pyridinepropanal (0.3 g, prepared according to the method of example 3 of International Application No. WO-A-92 / 19593) in anhydrous tetrahydrofuran (15 ml) and stirring was -78. Continue for 5 minutes at < 0 > C, then leave to warm to room temperature. The reaction was stopped with saturated aqueous ammonium chloride solution and extracted with diethyl ether (3 x 30 ml). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow gum, which was further purified by reverse phase HPLC to give the title compound as a pale yellow gum (0.11 g).

MS (APCI) 346 (M + H) ⁺

¹ H NMR (DMSO) 8.4 (1 H, d); 8.35 (1 H, doublet of doublets); 7.65-7.50 (5H, m); 7.43 (2H, t); 7.35-7.2 (2H, m); 7.1 (2H, d); 5.1 (1H, d); 3.9-3.8 (1 H, m); 2.9-2.55 (2H, m); 2.05-1.9 (1 H, m); 1.75-1.6 (1 H, m); 1.15-1.05 (1 H, m); 0.95-0.88 (1 H, m); 0.82-0.70 (2H, m).

Example 10

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol and (2R, 3S) -4- (6-bromonaphthalene- 2-yloxy) -1-pyridin-3-yl-pentan-3-ol

a) (2S) -2- (6-bromonaphthalen-2-yloxy) propionic acid ethyl ester

Of 2-hydroxy-6-bromonaphthalene (11.2 g), R-(+)-ethyl lactate (5.93 g), triphenylphosphine (13.15 g) and diethylazodicarboxylate (9.61 g) Prepared according to the method described in Example 1a from a solution in anhydrous tetrahydrofuran (120 ml). The crude product was purified by silica column chromatography eluting with dichloromethane: hexanes (1: 4 to 2: 3) to give the subtitle compound as a solid (12.45 g).

m.p. 72-74 ℃

GC / MS 322-324 [M] ⁺

¹ H NMR (DMSO) 8.13 (1 H, d); 7.85 (1 H, d); 7.75 (1 H, d); 7.57 (1 H, doublet of double); 7.25 (2H, d); 5.12 (1 H, q); 4.16 (2H, q); 1.57 (3 H, d); 1.17 (3 H, t).

b) (2S) -2- (6-bromonaphthalen-2-yloxy) -propan-1-ol.

Example 4b from (2S) -2- (6-bromonaphthalen-2-yloxy) -propionic acid ethyl ester (12.45 g, Example 10a) and sodium borohydride (1.6 g) in ethanol (150 ml) It was prepared according to the method described in. This crude material was purified by silica column chromatography eluting with ethanol: dichloromethane (1:99) to give a subtitle compound as a solid (10.5 g).

m.p. 71-72 ℃

GC / MS 280-282 [M] ⁺

¹ H NMR (CDCl ₃ ) 7.92 (1 H, d); 7.67 (1 H, doublet of double); 7.59 (1 H, d); 7.50 (1 H, doublet of double); 7.18 (2H, doublet of double); 4.70-4.61 (1 H, m); 3.87-3.74 (2H, m); 2.02 (1H, broad singlet); 1.35 (3 H, d).

c) (2S, 3RS) -4- (6-bromo-naphthalen-2-yloxy) -1-pyridin-3-yl-pent-1-yn-3-ol

(2S) -2- (6-bromonaphthalen-2-yloxy) -propan-1-ol (5 g, Example 10b), oxalyl chloride (2.9 g), dimethyl sulfoxide (2.64 g), trimethyl Prepared according to the method described in Example 1c) from amine (11.43 g), n-butyllithium (2.5 M in hexane, 12 ml) and 3-pyridylacetylene (3.15 g) as a 4: 1 mixture of diastereomers A subtitle compound was obtained (4.4 g).

MS (APCI) 383 (M + H) ⁺

¹ H NMR (CDCl ₃ major diastereomer) 8.75 (1H, d); 8.54 (1H, doublet of double); 7.93 (1 H, d); 7.75-7.66 (2H, m); 7.60 (1 H, d); 7.51 (1H, doublet of double); 7.49-7.20 (3H, m); 4.88 (1 H, broad singlet); 4.80-4.72 (1 H, m); 3.23 (1H, broad singlet); 1.55 (3 H, d).

d) (2S, 3RS) -4- (6-Bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol

(2S, 3RS) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pent-1-yn-3-ol (2.78 g, Example 10c) and ethyl acetate ( 150 ml) was prepared according to the method described in Example 1d from 5% rhodium on carbon (1.5 g) at 2 atmospheres to give a subtitle compound which was an oil as a 4: 1 mixture of diastereomers (2.6 g).

MS (APCI) 383 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, doublet of doublets); 7.91 (1 H, d); 7.66 (1 H, d); 7.56 (1 H, dt); 7.50 (2H, doublet of single); 7.26-7.20 (1 H, m); 7.16-7.09 (2H, m); 4.50-4.47 (1 H, m); 3.92-3.87 (1 H, m); 2.96-2.92 (1 H, m); 2.80-2.73 (1 H, m); 2.20 (1H, broad singlet); 1.92-1.84 (2H, m); 1.35 (3 H, d).

e.e. 44% (estimated by HPLC using a Chiralpak AD column and eluted with isohexane: ethanol (60:40)).

e) 5-oxo-pyridine-1,2-dicarboxylic acid 1-benzyl ester (2R, 3S) -2- [2- (6-bromonaphthalen-2-yloxyl) -1- (2-pyridine -3-yl-ethyl) propyl] ester and 5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2S, 3R) -2- [2- (6-bromonaphthalene-2 -Oxyl) -1- (2-pyridin-3-yl-ethyl) propyl] ester.

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol, (2R, 3S) -4- (6-bromonaphthalene- 2-yloxy) -1-pyridin-3-yl-pentan-3-ol (1.5 g, Example 10d), 5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2.05 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 g) and 4-dimethylaminopyridine (0.95 g) were stirred overnight in dichloromethane (50 ml) at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with ethyl acetate: hexanes (4: 1) to give an oil (2.3 g). This diastereomer is separated by standard phase HPLC eluting with ethyl acetate: hexane (4: 1) to give a subtitle compound.

5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2S, 3R) -2- [2- (6-bromonaphthalen-2-yloxyl) -1- (2-pyridine -3-yl-ethyl) -propyl] ester (1.46 g of main diastereomer isomerized second).

MS (APCI) 632 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.46 (1 H, dd); 8.42 (1 H, d); 7.91 (1 H, d); 7.64 (1 H, d); 7.55 (2H, d); 7.50 (1 H, d); 7.45-7.26 (5H, m); 7.20 (1 H, t); 7.08 (1 H, d); 7.05 (1 H, s); 5.29 (2H, d); 5.18-5.15 (1 H, m); 4.75 (1H, doublet of single); 4.63-4.53 (1 H, m); 2.69-2.30 (5H, m); 2.05-1.92 (3H, m); 1.31 (3 H, d).

5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2R, 3S) -2- [2- (6-bromonaphthalen-2-yloxyl) -1- (2-pyridine -3-yl-ethyl) propyl] ester (0.37 g of the first diastereoisomer being eluted).

MS (APCI) 632 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.47 (1 H, dd); 8.45 (1 H, d); 7.91 (1 H, d); 7.64 (1 H, d); 7.52 (2H, d); 7.48 (1 H, d); 7.34-7. 26 (5H, m); 7.20 (1 H, t); 7.07-7. 01 (2H, m); 5.21-5.19 (2H, m); 4.75 (1H, doublet of single); 4.65-4.55 (1 H, m); 2.78-2.25 (5H, m); 2.18-1.92 (3H, m); 1.35 (3 H, d).

f) (2S, 3R) -4- (6-bromo-naphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol

5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2S, 3R) -2- [2- (6-bromonaphthalen-2-yloxyl) -1- (2-pyridine -3-yl-ethyl) propyl] ester (1.46 g Example 10e) and potassium carbonate (0.96 g) were stirred overnight at room temperature in methanol (24 ml) and water (1 ml). The reaction mixture was concentrated under reduced pressure and the residue was separated between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue triturated in ether: hexanes (1: 1) to give the title compound as a solid (0.7 g).

m.p. 117-118 ℃

MS (APCI) 388 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, doublet of doublets); 7.91 (1 H, d); 7.66 (1 H, d); 7.56 (1 H, dt); 7.50 (2H, doublet of single); 7.26-7.20 (1 H, m); 7.16-7.09 (2H, m); 4.50-4.47 (1 H, m); 3.92-3.87 (1 H, m); 2.96-2.92 (1 H, m); 2.80-2.73 (1 H, m); 2.20 (1H, broad singlet); 1.92-1.84 (2H, m); 1.35 (3 H, d).

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol

5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (2R, 3S) -2- [2- (6-bromonaphthalene-2- in methanol (14 ml) and water (1 ml) Iloxyl) -1- (2-pyridin-3-yl-ethyl) propyl] ester (0.37 g Example 10e) and potassium carbonate (0.24 g) were prepared according to the method described in Example 10f to give the title compound. Obtained as a solid (0.15 g).

m.p. 116-117 ℃

MS (APCI) 388 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1 H, doublet of doublets); 7.91 (1 H, d); 7.66 (1 H, d); 7.56 (1 H, dt); 7.50 (2H, doublet of single); 7.26-7.20 (1 H, m); 7.16-7.09 (2H, m); 4.50-4.47 (1 H, m); 3.92-3.87 (1 H, m); 2.96-2.92 (1 H, m); 2.80-2.73 (1 H, m); 2.20 (1H, broad singlet); 1.92-1.84 (2H, m); 1.35 (3 H, d).

Example 11

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid

a) (3S, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol

5 on (3RS, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pent-1-yn-3-ol (5.93 g, Example 4c) and activated carbon (2.0 g) % Rhodium was prepared in ethyl acetate (100 ml) according to the method described in Example 1d to give a subtitle compound as a mixture of oil and diastereomer 4: 1 (5.6 g). This diastereomer is separated using standard phase HPLC eluting with 3% isopropyl alcohol in dichloromethane and is used as (2S, 3R) -2- (4-bromophenoxy) -5- as the main diastereomer. Pyridin-3-yl-pentan-3-ol (3.21 g) and the second eluted and minor diastereoisomer (2S, 3S) -2- (4-bromophenoxy) -5-pyridin-3-yl- Pentane-3-ol (0.71 g) was obtained.

MS (APCI) 336/388 (M + H) ⁺

¹ H NMR (CDCl ₃ , major diastereomer) 8.50 (1H, d); 8.45 (1 H, doublet of doublets); 7.54 (1 H, dt); 7.37 (2H, d); 7.22 (1H, doublet of double); 6.76 (2H, d); 4.30-4.27 (1 H, m); 3.82 (1 H, p); 2.94-2.89 (1 H, m); 2.77-2.70 (1 H, m); 2.18 (1 H, broad singlet); 1.86-1.78 (2H, m); 1.26 (3 H, d).

b) (3R, 4S) -3- [4- (4-bromophenoxy) -3- (tert-butyldimethylsilanyloxy) pentyl] pyridine

(3S, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (2.01 g, Example 5a), tert-butyldimethylsilyl chloride (1.81 g) And imidazole (0.814 g) in dry dichloromethane according to the method described in Example 5a and after column chromatography eluting with dichloromethane: diethyl ether (1: 1) to give a subtitle compound as an oil (2.52). g).

MS (APCI) 450/452 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.45-8.42 (2H, m); 7.4 (1 H, dt); 7.35 (2H, d); 7.22-7.18 (1 H, m); 6.73 (2H, d); 4.23-4.20 (1 H, m); 3.82-3.78 (1 H, m); 2.84-2.62 (2H, m); 1.96-1.88 (1 H, m); 1.82-1.78 (1 H, m); 1.27 (3 H, d); 0.94 (9H, s); 0.12 (3H, s); 0.09 (3H, s).

c) (1S, 2R) -4- [2-tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzenebromic acid

tert-butyllithium (3.95 ml, 1.7 M in hexane), (3R, 4S) -3- [4- (4-bromophenoxy) -3- (tert-butyldimethylsilanyloxy) pentyl] pyridine ( 2.52 g, Example 11b) and tri-isopropylborate (1.68 ml) were prepared in tetrahydrofuran (20 ml) according to the method described in Example 5b to ethyl acetate and then ethyl acetate: methanol (4: 1) After elution silica chromatography, the subtitle compound was obtained as a foam (1.22 g).

MS (APCI) 416 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.60-8.53 (2H, m); 7.95 (2H, d); 7.6-7.54 (1 H, m); 7.26-7. 22 (1 H, m); 6.86 (2H, d); 4.33-4.27 (1 H, m); 3.93-3.86 (1 H, m); 2.82-2.62 (2H, m); 1.98-1.75 (2H, m); 1.28 (3 H, d); 0.94 (9H, s); 0.08 (6 H, s).

Example 12

(1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N-methylacetamide

a) 2- (3-bromophenyl) -N-methyl-acetamide

3-bromophenyl acetic acid (2.15g), tetrahydrofuran solution of methyl amine (6ml, 2M), dimethylaminopyridine (1.32g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochlor The solution of reed (2.06 g) in dichloromethane was stirred for 16 h at room temperature. The organic solution was washed twice with 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to give a solid (1.86 g).

MS (APCI) 228/230 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.44 (2H, m); 7.21 (2H, m); 5.39 (1H, broad singlet); 3.54 (2H, s); 2.79 (3 H, d).

b) (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N-methylacetamide

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 2- Toluene (5 ml) of (3-bromophenyl) -N-methyl-acetamide (0.21 g, Example 12a), 2 M aqueous sodium carbonate solution (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) ) And ethanol (2 ml) solution were heated at 100 ° C for 4 h. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the residue in solution in methanol (5 ml). This suspension was stirred at rt for 18 h. The mixture was concentrated under reduced pressure and the residue was separated between ether and water. The aqueous layer was neutralized and extracted with dichloromethane (2 x 50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting in a 0-25% ethanol gradient in dichloromethane to give the title compound as an oil (0.15 g).

MS (APCI) 405 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.54 (1 H, m); 7.52 (2H, d); 7.47-7.46 (1 H, m); 7.43-7.38 (2H, m); 7.24-7.18 (2H, m); 6.95 (2H, d); 5.40 (1H, broad singlet); 4.40-4.37 (1 H, m); 3.88-3.85 (1 H, m); 3.63 (2H, s); 2.98-2.91 (1 H, m); 2.77 (3H, d); 2.74-2.68 (1 H, m); 2.16 (1 H, d); 1.89-1.82 (2H, m) 1.31 (3H, d).

Example 13

(3R, 4S) -4- (4'-Chloro-2'-fluorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

(1S, 2R) -4- [2-tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 1-bromo- A solution of 4-chloro-2-fluorobenzene (0.21 g), 2 M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml) From the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure.

Concentrated hydrochloric acid (1 ml) was added to the residue solution in methanol (5 ml) and the suspension was stirred at room temperature for 6 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil (0.13 g).

MS (APCI) 386 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.45 (1 H, doublet of doublets); 7.56-7.54 (1 H, m); 7.43 (2H, doublet of single); 7.33 (1 H, t); 7.26-7. 15 (3H, m); 6.94 (2H, d); 4.41-4.37 (1 H, m); 3.87-3.86 (1 H, m); 3.00-2.95 (1 H, m); 2.80-2.75 (1 H, m); 2.15 (1 H, d); 1.87-1.84 (2H, m); 1.31 (3 H, d).

Example 14

(3R, 4S) -4- (4'chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 4-chloro- Description of Example 12b from a solution in toluene (4 ml) and ethanol (1 ml) of iodobenzene (0.24 g), 2 M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) Prepared according to one method. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 3 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a gum from which an oxalate salt was made (0.11 g).

m.p. 133-135 ℃

MS (APCI) 368 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, s); 8.38 (1 H, d); 7.63-7. 62 (3H, m); 7.56 (2H, d); 7.46 (2H, d); 7.3 (1 H, q); 7.00 (2H, d); 5.00 (1 H, d); 4.37-4.3 (1 H, m); 3.6-3.5 (1 H, m); 2.87-2.75 (1 H, m); 2.7-2.6 (1 H, m); 1.93-1.80 (1 H, m); 1.7-1.6 (1 H, m); 1.24 (3 H, d).

Example 15

(3R, 4S) -4- (5'-methoxy-2'methylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 4-bromo Example from a solution in toluene (4 ml) and ethanol (1 ml) of -3-methylanisole (0.2 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) Prepared according to the method described in 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 6 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a gum from which an oxalate salt was made (0.11 g).

m.p. 86-88 ℃

MS (APCI) 377 (M + H) ⁺ (free base)

¹ H NMR (DMSO) 8.47 (1 H, s); 8.41 (1 H, d); 7.68 (1 H, d); 7.34 (1 H, q); 7.16 (2H, d); 7.07 (1 H, d); 6.92 (2H, d); 6.85-6.75 (2H, m); 4.29 (1 H, t); 3.75 (3 H, s); 3.6-3.5 (1 H, m); 2.9-2.7 (2H, m); 2.2 (3H, s); 1.95-1.8 (1 H, m); 1.72-1.6 (1 H, m); 1.24 (3 H, d).

Example 16

(3R, 4S) -4- (3 ', 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, oxalic acid salt

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3,4- In Example 12b from a solution in toluene (5 ml) and ethanol (1 ml) of dichloroiodobenzene (0.273 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) Prepared according to the method described. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol: water (4: 1) (5 ml) and the suspension was stirred at room temperature for 3 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a gum from which an oxalate salt was made (0.23 g).

m.p. 86.4-88.4 ℃

MS (APCI) 402/404 (M + H) ⁺ (free base)

¹ H NMR (DMSO) 8.51 (1 H, d); 8.46 (1 H, doublet of doublets); 7.62 (1 H, d); 7.55 (1 H, dt); 7.48-7.45 (3H, m); 7.36 (1 H, doublet of double); 7.23 (1 H, doublet of double); 6.93 (2H, d); 4.39 (1 H, dq); 3.87-3. 85 (1 H, m); 2.95-2.91 (1 H, m); 2.76-2.77 (1 H, m); 2.21 (1H, broad singlet); 1.89-1.84 (2H, m); 1.30 (3 H, d).

Example 17

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-morpholin-4-ylethyl) amide.

a) 3-bromo-N- (2-morpholin-4-yl-ethyl) -benzenesulfonamide hydrochloride

To a stirred solution of 3-bromobenzenesulfonyl chloride (5.0 g) in ether (50 ml) was added dropwise 4- (2-aminoethyl) morpholine (2.54 g) at 5 ° C. The resulting suspension was stirred for 30 minutes and filtered to give the subtitle compound as a solid (4.45 g).

m.p. 82.4-84.0 ℃

MS (APCI) 349/351 (M + H) ⁺ (Free Base)

¹ H NMR (DMSO) 7.96 (1 H, t); 7.88-7. 80 (3H, m); 7.56 (1 H, t); 3.59 (2H, t); 3.50 (2H, t); 2.92 (2H, t); 2.39 (2H, t); 2.35-2.20 (2H, broad singlet).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-morpholin-4-ylethyl) amide .

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3-bromo -N- (2-morpholin-4-yl-ethyl) -benzenesulfonamide hydrochloride (0.385 g, Example 17a), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0 (0.025 g) in toluene (5 ml) and ethanol (1 ml) was prepared according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol: water (4: 1) (5 ml) and the suspension was stirred at room temperature for 3 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a gum, from which an oxalate salt as a gum was prepared (0.295 g).

MS (APCI) 526 (M + H) ⁺ (free base)

¹ H NMR (DMSO) 8.46 (1 H, d); 8.41 (1 H, doublet); 7.99 (1 H, d); 7.90 (2H, dt); 7.74 (1 H, doublet of double); 7.69-7.64 (4H, m); 7.33 (1 H, doublet of single); 7.05 (2H, d); 4.36 (1 H, p); 3.69-3.66 (4H, m); 3.58-3.54 (1 H, m); 3.10-3.04 (2H, broad singlet); 2.90-2.81 (7H, broad singlet); 2.75-2.61 (2H, m); 1.94-1.80 (2H, m); 1.76-1.62 (2H, m); 1.25 (3 H, d).

Example 18

(3R, 4S) -4- (2 ', 4'dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 1-bromo -2,4-dichlorobenzene (0.218 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in solution in toluene (5 ml) and ethanol (2 ml) Prepared according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours under nitrogen. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was neutralized with sodium hydrogen carbonate solution (in water) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a solid (0.064 g) from which an oxalate salt was made (0.054 g).

m.p. 98-100 ℃

MS (APCI) 402.1, 404.1, 405.1 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (2H, m); 7.69 (2H, bs); 7.49-7.32 (5H, m); 7.00 (2H, d); 4.34 (1 H, m); 3.38 (1 H, m); 2.83 (1 H, m); 2.70 (1 H, m); 1.86 (1 H, m); 1.66 (1 H, m); 1.25 (3 H, d).

Example 19

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid methylamide.

a) 3-bromo-N-methyl-benzenesulfonamide

Methyl amine was bubbled through a solution of 3-bromobenzenesulfonyl chloride (5.0 g) in tetrahydrofuran (50 ml) at 0 ° C. The resulting suspension was stirred for 3 hours, filtered and concentrated under reduced pressure. The residue was triturated with hexane and filtered to give the subtitle compound as a solid (4.52 g).

m.p. 88-89 ℃

MS (APCI) 250 (M + H) ⁺ (free base)

¹ H NMR (DMSO) 8.02 (1 H, m); 7.80 (1 H, m); 7.72 (1 H, m); 7.42 (1 H, t); 4.44 (1 H, b m); 2.70 (3 H, d).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid methylamide

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3-bromo -N-methyl-benzenesulfonamide (0.240 g, Example 19a), 2M aqueous sodium carbonate solution (0.55 ml) and toluene (5 ml) and ethanol (2 ml) of tetrakis (triphenylphosphine) palladium (0) (0.020 g) From a solution) was prepared according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (4 ml) and the suspension was stirred at rt for 1.5 h. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was basified with 10% sodium hydrogen carbonate and the aqueous solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a foam (0.0495 g).

MS (APCI) 427.1 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, m); 8.39 (1 H, dt); 7.95 (1 H, d); 7.89 (1 H, dt); 7.72-7.60 (4H, m); 7.47 (1 H, q); 7.30 (1 H, doublet of double); 7.05 (2H, d); 5.01 (1 H, d); 4.36 (1 H, m); 3.56 (1 H, m); 2.82 (1 H, m); 2.67 (1 H, m); 2.43 (3H, d); 1.87 (1 H, m); 1.65 (1 H, m); 1.25 (3 H, d).

Example 20

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-pyrrolidin-1-ylethyl) amide.

a) 3-bromo-N- (2-pyrrolidin-1-yl-ethyl) benzenesulfonamide hydrochloride

N- (2-aminoethyl) pyrrolidine (1.61 g) was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (3.61 g) in diethyl ether (100 ml) at room temperature. The resulting suspension was stirred for 30 minutes and filtered to give the subtitle compound in solid form (4.48 g).

m.p. 144-146 ℃

MS (APCI) 333/335 [M-HCl] ⁺

¹ H NMR (DMSO) 8.28 (1 H, bs); 7.99 (1 H, m); 7.93-7. 84 (2H, m); 7.60 (1 H, t); 3.3-2.9 (8H, bm); 1.88 (4 H, bs).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-pyrrolidin-1-ylethyl) amides.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3-bromo -N- (2-pyrrolidin-1-yl-ethyl) benzenesulfonamide hydrochloride (0.355 g, Example 20a), 2M aqueous sodium carbonate solution (0.55 ml) and tetrakis (triphenylphosphine) palladium (0 (0.020 g) in toluene (5 ml) and ethanol (1 ml) was prepared according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (4 ml) and the suspension was stirred at room temperature for 0.75 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was basified with sodium hydrogen carbonate solution and the aqueous solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a foam (0.113 g).

MS (APCI) 510.1 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, m); 8.39 (1 H, m); 8.00 (1 H, m); 7.86 (1 H, dt); 7.72 (1 H, m); 7.63 (4 H, m); 7.30 (1 H, doublet of double); 7.05 (2H, d); 5.01 (1 H, d); 4.36 (1H, quintet); 3.57 (1 H, m); 2.92 (2H, t); 2.89 (1 H, m); 2.67 (1 H, m); 2.40 (2H, t); 2.31 (4H, m); 1.87 (1 H, m); 1.63 (1 H, m); 1.58 (4 H, m); 1.25 (3 H, d).

Example 21

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carbonitrile.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 4-bromo Example from a solution in toluene (5 ml) and ethanol (2 ml) of 3-methylbenzonitrile (0.20 g), 2 M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) Prepared according to the method described in 12b. The reaction mixture was heated at 100 ° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was neutralized with saturated sodium bicarbonate solution in water and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil (0.15 g).

MS (APCI) 373 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.64 (1 H, doublet of double); 7.53 (3 H, m); 7.25 (4 H, m); 6.94 (2H, d); 4.40 (1 H, m); 3.87 (1 H, m); 2.96 (1 H, m); 2.75 (1 H, m); 2.30 (3H, s); 2.17 (1 H, broad singlet); 1.88 (2H, m); 1.33 (3 H, d).

Example 22

(1S, 2R) -N- [2-Chloro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide, oxalic acid salt

(3R, 4S) -4- (4'-Amino-2'-chloro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, oxalate

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 4-bromo Example from a solution in toluene (5 ml) and ethanol (2 ml) of 3-chloroacetanilide (0.20 g), 2 M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) Prepared according to the method described in 12b. The reaction mixture was heated at 100 ° C. for 4 hours under nitrogen. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to the solution of the residue in methanol (5 ml) and the suspension was stirred at rt for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was neutralized with saturated sodium bicarbonate solution in water and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give two products. The first is the oily title compound (0.05 g) from which an oxalate salt was prepared as a foam (0.05 g).

MS (APCI) 425 (M + H) ⁺

¹ H NMR (DMSO) 10.16 (1H, s); 8.47 (1 H, s); 8.41 (1 H, d); 7.88 (1 H, d); 7.68 (1 H, d); 7.49 (1 H, doublet of double); 7.35-7.29 (3H, m); 6.96 (2H, d); 6.68 (1 H, doublet of double); 4.32 (1 H, m); 3.56 (1 H, m); 2.82 (1 H, m); 2.66 (1 H, m); 2.07 (3H, s); 1.86 (1 H, m); 1.66 (1 H, m); 1.25 (3 H, d).

On further elution, secondly compound (3R, 4S) -4- (4'-amino-2'-chloro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.10 g) was obtained as an oil, from which a solid oxalate salt was prepared (0.10 g).

m.p. 142-145 ℃

MS (APCI) 383 (M + H) ⁺

¹ H NMR (DMSO) 8.47 (1 H, d); 8.42 (1 H, doublet); 7.70 (1 H, d); 7.35 (1 H, m); 7.22 (2H, d); 7.00 (1 H, d); 6.91 (2H, d); 6.68 (1 H, d); 6.55 (1 H, doublet of double); 4.28 (1 H, m); 3.54 (1 H, m); 2.80 (1 H, m); 2.69 (1 H, m); 1.87 (1 H, m); 1.64 (1 H, m); 1.24 (3 H, d).

Example 23

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-dimethylaminoethyl) amide.

a) 3-bromo-N- (2-dimethylamino-ethyl) benzenesulfonamide hydrochloride.

N, N-dimethylethylenediamine (1.76 g) was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (5.11 g) in diethyl ether (100 g) at room temperature. The resulting suspension was stirred for 30 minutes and filtered to give the subtitle compound as a solid (4.31 g).

m.p. 154-156 ℃

MS (APCI) 305/307 [(M-HCl) < + >] ⁺

¹ H NMR (DMSO) 8.32 (1 H, bs); 8.00 (1 H, m); 7.95-7. 85 (2H, m); 7.60 (1 H, t); 3.15 (4H, s); 2.75 (6H, s)

b) (1S, 2R) -4 '(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-dimethylaminoethyl) amide.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3-bromo -N- (2-dimethylamino-ethyl) benzenesulfonamide hydrochloride (0.331 g, Example 23a), 2M aqueous sodium carbonate solution (0.723 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) Was prepared according to the method described in Example 12b from a solution in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 110 ° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a colorless oil.

MS (APCI) 484 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, s); 8.45 (1 H, d); 8.05 (1 H, t); 7.80 (1 H, doublet); 7.75 (1 H, doublet of doublets); 7.60-7.5 (4 H, m); 7.30-7.20 (1 H, m); 7.00 (2H, d); 4.45-4.35 (1 H, m); 3.95-3.80 (1 H, m); 3.05-2.80 (3H, m); 2.80-2.70 (1 H, m); 2.40-2.30 (2H, m); 2.10 (6H, s); 1.90-1.80 (4H, m); 1.30 (3 H, d).

Example 24

(1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide.

a) 2- (3-bromophenyl) -N-methyl-acetamide

2M solution of methylamine in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 4-hydrochloride (8.88 g), 4-dimethylaminopyridine (5.67 g) and tetrahydrofuran (23 ml) To a solution of 4-bromophenylacetic acid (5.0 g) in methane (100 ml). This mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3 × 100 ml) and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. A subtitle compound was obtained as a solid after recrystallization from 1% hexane in ethyl acetate (4.74 g).

m.p. 117-118 ℃

MS (APCI) 228/230 (M + H ⁺ )

¹ H NMR (CDCl ₃ ) 7.96 (1 H, s); 7.48 (2H, d); 7.20 (2 H, d); 3.40 (2H, s); 2.60 (3 H, d).

b) (1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 2- (3 -Bromophenyl) -N-methyl-acetamide (0.244 g, Example 24a), 2M aqueous sodium carbonate solution (0.265 ml) and toluene (5 ml) of tetrakis (triphenylphosphine) palladium (0) (0.1 g) And from a solution in ethanol (2 ml) according to the method described in Example 12b. The reaction mixture was heated at 110 ° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml) and concentrated hydrochloric acid (1 ml) was added and the solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure and the residue was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to give the title compound as an oil, which was treated with a saturated ether solution of oxalic acid to convert to an oxalic acid salt to give the title compound as a gum ( 0.123 g).

MS (APCI) 405 [(M + H) -Oxalate] ⁺

¹ H NMR (DMSO) 8.45 (1 H, s); 8.40 (1 H, d); 7.95 (1 H, d); 7.70 (1 H, d); 7.50 (4H, dt); 7.35 (1 H, doublet of double); 7.30 (2H, d); 7.0 (2H, d); 4.35-4.30 (1 H, m); 3.55-3.50 (1H, m); 3.45-3.40 (2H, m); 2.85-2.75 (1 H, m); 2.70-2.60 (1 H, m); 2.55 (3H, d); 1.85-1.80 (1 H, m); 1.70-1.55 (1 H, m); 1.25 (3 H, d).

Example 25

(1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide.

a) 2- (3-bromophenyl) -N, N-dimethyl-acetamide.

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 4-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), 2M solution of dimethylamine in tetrahydrofuran (10 ml) and dichloromethane Prepared according to the method described in Example 24a from a solution of 3-bromophenylacetic acid (2.15 g) in (100 ml). The mixture was stirred at rt overnight. The reaction mixture was washed with 2M hydrochloric acid (3 × 100 ml) and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The subtitle compound as an oil was obtained (2.89 g).

MS (APCI) 242/244 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.45-7.35 (2H, m); 7.20-7.15 (2H, m); 3.65 (2H, s); 3.05 (3H, s); 2.95 (3 H, s).

b) (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 2- (3 -Bromophenyl) -N, N-dimethyl-acetamide (0.234 g, Example 25a), 2M aqueous sodium carbonate solution (0.241 ml) and toluene (0 g) of tetrakis (triphenylphosphine) palladium (0) (0.1 g) 5 ml) and a solution in ethanol (2 ml) were prepared according to the method described in Example 12b. The reaction mixture was heated at 110 ° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.144 g).

MS (APCI) 419 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.45 (1 H, d); 7.55 (1 H, d); 7.50 (2H, d); 7.45 (2 H, d); 7.35 (1 H, t); 7.25-7. 15 (2H, m); 6.95 (2H, d); 4.45-4.35 (1 H, m); 3.90-3.80 (1 H, m); 3.75 (2H, s); 3.00 (3H, s); 2.95 (3H, s); 2.95-2.90 (1 H, m); 2.80-2.65 (1 H, m); 2.20 (1 H, d); 1.90-1.80 (2H, m); 1.25 (3 H, d).

Example 26

(4S, 3R) -4- (4'-Methanesulfonyl-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.25 g, Example 11c), 4-bromo Example by heating at 90 ° C. for 4 hours from a solution of phenylmethylsulfone (0.19 g), 2M aqueous sodium carbonate solution (0.64 ml) and tetrakis (triphenylphosphine) palladium (0) (0.016 g) in ethanol (3 ml) Prepared according to the method described in 12b. After cooling, the solution was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give an oil. Concentrated hydrochloric acid (1 ml) was added to an oil solution in methanol (5 ml). This solution was stirred at rt for 18 h. This mixture was concentrated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid (0.17 g).

MS (APCI) 412 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.44 (1 H, d); 8.39 (1 H, doublet of double); 7.95 (2H, d); 7.88 (2H, d); 7.69-7.61 (3H, m); 7.32-7.29 (1 H, m); 7.04 (2H, d); 5.01 (1 H, d); 4.38-4.35 (1 H, m); 3.57-3.55 (1 H, m); 3.24 (3H, s); 2.81-2.67 (2H, m); 1.94-1.79 (1 H, m); 1.72-1.57 (1H, m); 1.25 (3 H, d).

Example 27

(3R, 4S) -4- [3 '-(2-dimethylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol

a) [2- (3-bromophenyl) ethyl] dimethylamine hydrochloride.

Borane (1.0M, 24.7 ml) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 2- (3-bromophenyl) -N, N-dimethyl-acetamide (1.5 g, Example 25a) at 0 ° C. . After all addition, the solution was refluxed at 90 ° C. for 20 hours. After cooling this solution to room temperature, it was acidified with hydrochloric acid (6M, 10 ml) and further refluxed. The solution was cooled to room temperature and extracted with diethyl ether. The aqueous layer was basified with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. Treatment with 4M hydrogen chloride solution in dioxane converted the residue to hydrochloride salt to give a subtitle compound as a hygroscopic gum (0.949 g).

MS (APCI) 228/230 [(M-HCl) + H] ⁺

¹ H NMR (DMSO) 7.63 (1 H, s); 7.55-7.45 (1 H, m); 7.35-7.25 (2H, m); 3.28-3.24 (2H, m); 3.05-3.00 (2H, m); 2.84 (6 H, s).

b) (3R, 4S) -4- [3 '-(2-dimethylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), [2- ( 3-bromophenyl) ethyl] dimethylamine hydrochloride (0.21 g, Example 27a), 2M aqueous sodium carbonate solution (0.82 ml) and toluene (5 ml) of tetrakis (triphenylphosphine) palladium (0) (0.1 g) ) And in solution in ethanol (2 ml) according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Conc. Hydrochloric acid (1 ml) was added to the residue solution in methanol (5 ml) and the solution was stirred at room temperature for 2 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as an oil (0.07 g).

MS (APCI) 405 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1 H, doublet of doublets); 7.57-7.54 (1 H, m); 7.50 (2H, d); 7.39-7. 31 (3H, m); 7.24-7. 17 (2H, m); 6.95 (2H, d); 4.40-4.37 (1 H, m); 3.95-3.85 (1 H, m); 2.95-2.90 (1 H, m); 2.88-2.85 (2H, m); 2.76-2.71 (1 H, m); 2.67-2.61 (2H, m); 2.36 (6H, s); 2.10 (1 H, broad singlet); 1.89-1.81 (2H, m); 1.31 (3 H, d).

Example 28

(1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -1-morpholin-4-yl-ethanone oxalic acid salt.

a) 3-bromophenyl-1-morpholin-4-yl-ethanone.

3 in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 4-hydrochloride (0.764 g), 4-dimethylaminopyridine (0.488 g), morpholine (0.35 ml) and dichloromethane (10 ml) Prepared according to the method described in Example 24a from bromophenylacetic acid (0.43 g) solution. The mixture was stirred at rt overnight. The reaction mixture was washed with 2M hydrochloric acid (3 x 100 ml) and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The subtitle compound was obtained as a solid (0.550 g).

MS (APCI) 242/244 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.40 (2H, m); 7.17 (2H, m); 3.70 (2H, s); 3.65 (4H, s); 3.53 (2H, m); 3.45 (2H, m).

b) (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -1-morpholin-4-yl-ethane Warm, oxalate.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), 3-bromo Toluene (5 ml) of phenyl-1-morpholin-4-yl-ethanone (0.234 g, Example 28a), 2M aqueous sodium carbonate solution (0.241 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) ) And in solution in ethanol (2 ml) according to the method described in Example 12b. The reaction mixture was heated at 110 ° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml) and concentrated hydrochloric acid (1 ml) was added and the solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, and the residue was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.144 g).

MS (APCI) 419 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.45 (1 H, d); 7.55 (1 H, d); 7.50 (2H, d); 7.45 (2 H, d); 7.35 (1 H, t); 7.25-7. 15 (2H, m); 6.95 (2H, d); 4.45-4.35 (1 H, m); 3.90-3.80 (1 H, m); 3.75 (2H, s); 3.00 (3H, s); 2.95 (3H, s); 2.95-2.90 (1 H, m); 2.80-2.65 (1 H, m); 2.20 (1 H, d); 1.90-1.80 (2H, m); 1.25 (3 H, d).

Example 29

(3R, 4S) -4- [4- (3 '-(2-methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol

a) [2- (3-bromophenyl) ethyl] methylamine hydrochloride.

Borane (1.0 M, 26.3 ml) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 2- (3-bromophenyl) -N-methyl-acetamide (1.5 g, Example 12a) at 0 ° C. After all addition, the solution was refluxed at 90 ° C. for 20 hours. After cooling this solution to room temperature, it was acidified with hydrochloric acid (6M, 10 ml) and further refluxed. The solution was cooled to room temperature and extracted with diethyl ether. The aqueous layer was basified with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. Treatment with 4M hydrochloric acid solution in dioxane converted the residue to a hydrochloride salt to give a subtitle compound as a solid (0.727 g).

m.p. 135-136 ℃

MS (APCI) 214/216 [(M-HCl) + H] ⁺

¹ H NMR (DMSO) 9.00 (1 H, s); 7.51 (1 H, s); 7.50-7.45 (1 H, m); 7.35-7.25 (2H, m); 3.20-3.05 (2H, m); 3.00-2.90 (2H, m); 2.55 (3 H, s).

b) (3R, 4S) -4- [4- (3 '-(methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), [2- ( 3-bromophenyl) ethyl] methylamine hydrochloride (0.241 g, Example 29a), 2M aqueous sodium carbonate solution (0.72 ml) and toluene (5 ml) of tetrakis (triphenylphosphine) palladium (0) (0.1 g) ) And in solution in ethanol (2 ml) according to the method described in Example 12b. The reaction mixture was heated at 110 ° C. for 6 hours. After cooling, the solution is concentrated under reduced pressure and the residue is dissolved in methanol (10 ml). Concentrated hydrochloric acid (1 ml) was added and the solution was stirred for 18 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in 1% triethylamine in dichloromethane to give the title compound as an oil (0.14 g).

MS (APCI) 391 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, d); 8.45 (1 H, doublet of doublets); 7.55 (1 H, doublet of double); 7.50 (2H, doublet of single); 7.40-7.30 (3H, m); 7.25-7. 15 (2H, m); 6.95 (2H, d); 4.45-4.30 (1 H, m); 3.90-3.80 (1 H, m); 3.00 (4H, s); 2.95-2.90 (1 H, m); 2.80-2.65 (1 H, m); 2.50 (3H, s); 1.90-1.80 (2H, m); 1.30 (3 H, d).

Example 30

(3R, 4S) -4- [4 '-(2-methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol

a) [2- (4-bromophenyl) ethyl] -N-methylamine hydrochloride.

Borane in tetrahydrofuran (1.0 M, 35 ml), 4-bromophenyl acetic acid methylamide (2.0 g, Example 24a) in anhydrous tetrahydrofuran, prepared according to the method described in Example 29a, as a solid A subtitle compound was obtained (0.45 g).

m.p. 198-200 ℃

MS (APCI) 214 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.43 (2H, d); 7.12 (2 H, d); 3.25-3.09 (4H, m); 2.72 (3H, s).

b) (3R, 4S) -4- [4 '-(2-methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

[2- (4-Bromophenyl) ethyl] -N-methylamine hydrochloride (0.214 g, Example 30a), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate solution (0.5 ml), (1S , 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11) and tetrakis (triphenylphosphine Prepared according to the method described in Example 12b by heating from palladium (0) (0.02 g) at 120 ° C. for 4 hours. After completion of the reaction, the residue was purified by standard HPLC, eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a pale yellow solid (0.081 g).

m.p. 113-114 ℃

MS (APCI) 391 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, d); 8.38 (1 H, d); 7.62 (1 H, d); 7.51 (4H, t); 7.32-7.23 (3H, m); 6.97 (2H, d); 4.98 (1 H, d); 4.31 (1 H, q); 3.54 (1H, broad singlet); 2.89-2.73 (1 H, m); 2.71 (4H, s); 2.69-2.53 (1 H, m); 2.30 (3H, s); 1.91-1.79 (1 H, m); 1.72-1.59 (1 H, m); 1.23 (3 H, d).

Example 31

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl-urea.

3-bromophenylurea (0.215g), ethanol (1ml), toluene (4ml), 2M aqueous sodium carbonate solution (0.5ml), (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) 1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) were heated at 120 ° C. for 4 hours. Prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a solid (0.116 g).

m.p. 75-76 ℃

MS (APCI) 392 (M + H) ⁺

¹ H NMR (DMSO) 8.58 (1 H, s); 8.43 (2H, d); 7.64 (2H, d); 7.48 (2H, d); 7.32-7.23 (3H, m); 7.11 (1 H, d); 6.98 (2H, d); 5.87 (2H, d); 5.00 (1 H, d); 3.56 (1 H, d); 3.49-3.34 (1 H, m); 2.87-2.76 (1 H, m); 2.71-2.60 (1 H, m); 1.92-1.82 (1 H, m); 1.72-1.63 (1 H, m); 1.24 (3 H, d).

Example 32

(3R, 4S) -4- (3 ', 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol oxalic acid salt

3,4-dichloroiodobenzene (0.273g), ethanol (2ml), toluene (5ml), 2M aqueous sodium carbonate solution (0.5ml), (1S, 2R) -4- [2- (tert-butyldimethylsilanyl Oxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) for 4 hours at 120 ° C. Heated to prepare according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound, which was treated with a saturated ether solution of oxalic acid to be converted to oxalate to give the title compound as a solid. (0.229 g).

m.p. 86-88 ℃

MS (APCI) 402,404 (M + H) ⁺

¹ H NMR (DMSO) 8.46 (1 H, d); 8.44 (1 H, d); 7.87 (1 H, d); 7.70 (1 H, dt); 7.65-7.58 (4H, m); 7.35 (1 H, doublet of double); 7.0 (2H, d); 4.35 (1 H, dq); 3.60-3.52 (1 H, m); 2.88-2.78 (1 H, m); 2.72-2.61 (1 H, m); 1.95-1.82 (1 H, m); 1.70-1.59 (1 H, m); 1.25 (3 H, d).

Example 33

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid.

Solution of (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (10 g, Example 11) in methanol (150 ml) Was stirred for 2 h hydrochloric acid (25 ml) at room temperature for 16 h. The solution was concentrated to give an acidic aqueous residue which was washed with diethyl ether. The aqueous layer was basified with saturated sodium bicarbonate, the product was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as a foam (6.97 g).

MS (APCI) 302 (M + H) ⁺

¹ H NMR (DMSO / D ₂ O) 8.42 (1 H, s); 8.39 (1 H, s); 7.70-7.64 (3H, m); 7.33 (1 H, doublet of single); 6.85 (2H, d); 4.32 (1 H, m); 3.53 (1 H, m); 2.79 (1 H, m); 2.66 (1 H, m); 1.84 (1 H, m); 1.65 (1 H, m); 1.21 (3 H, d).

Example 34

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -3-methyl-biphenyl-4-carbonitrile

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 4-bromo-2-methylbenzonitrile ( 0.301 g), 2M aqueous sodium carbonate solution (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (3 ml) were prepared according to the method described in Example 12b. The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil which is crystallized under high vacuum for 24 hours. Trituration with diethyl ether gives the title compound as a solid (0.11 g).

m.p. 93.5-94.5 ℃

MS (APCI) 373.2 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, m); 8.38 (1 H, m); 7.79 (1 H, d); 7.34 (1 H, s); 7.68-7. 60 (4H, m); 7.31 (1 H, m); 7.02 (2H, d); 5.01 (1 H, d); 4.36 (1 H, m); 3.55 (1 H, m); 2.80 (1 H, m); 2.65 (1 H, m); 2.53 (3H, s); 1.86 (1 H, m); 1.64 (1 H, m); 1.24 (3 H, d).

Example 35

(1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide, and (1S, 2S)- 4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide.

a) 5-bromo-2-fluorophenylsulfonic acid amide

A mixture of 5-bromo-2-fluoronitrobenzene (11 g), iron (20 g) and ammonium chloride (20 g) was refluxed in ethanol (200 ml) and water (150 ml) for 1 hour. The reaction was cooled down, filtered and concentrated to 200 ml. The filtrate was extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was added to concentrated hydrochloric acid (20 ml) and cooled to -5 ° C. A saturated solution of sodium nitrite (3.88 g) in water (6 ml) was added dropwise at a rate that kept the temperature below 0 ° C. Magnesium chloride (8 g) was added (caution: exotherm) and the resulting mixture was added to a saturated solution of sulfur dioxide in acetic acid (40 ml) and toluene (20 ml) containing cupric chloride (2.75 g) at room temperature with stirring. The mixture was stirred for 60 minutes, poured into water and extracted with toluene. The combined toluene extracts were washed with water, dilute sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (50 ml) and ammonia (0.880, 10 ml) was added. The resulting mixture was stirred for 30 minutes and concentrated to give an aqueous residue, which was partitioned between ethyl acetate (30 ml) and water (30 ml). The aqueous residue was extracted in ethyl acetate (3 x 30 ml) and the combined extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with ether: hexanes (1: 4) and filtered to give the subtitle compound as a solid (6.37 g).

m.p. 153-154 ℃

MS (APCI) 254 (MH) ^-

¹ H NMR (CDCl ₃ ) 8.05 (1H, dd); 7.71-7.66 (1 H, m); 7.13 (1 H, dd); 5.11 (2H, s).

b) (1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide, and (1S, 2S ) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide.

5-bromo-2-fluorophenylsulfonic acid amide (0.191 g, Example 34a), ethanol (2 ml), toluene (5 ml), 2M aqueous sodium carbonate solution (0.5 ml), (1S, 2R) -4- [2 -(tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11) and tetrakis (triphenylphosphine) palladium (0) (0.025 g Was prepared according to the method described in Example 12b by heating at 80 ° C. for 2 hours. After the completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give the secondary diastereomer (1S, 2S) -4-fluoro-4 '-(2-hydrate). Roxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide is obtained as a foam and further eluted to give (1S, 2R) -4-fluoro-4 '-(as the main product. 2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide was obtained (0.15 g).

(1S, 2S) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide

MS (APCI) 431 (M + H) ⁺

¹ H NMR (DMSO) 8.43 (1 H, d); 8.37 (1 H, doublet of doublets); 7.94 (1 H, doublet of double); 7.89-7. 85 (1 H, m); 7.71 (2H, s); 7.64-7.61 (1 H, m); 7.56 (2H, d); 7.50-7.44 (1H, m); 7.30-7.26 (1 H, m); 7.04 (2H, d); 4.97 (1 H, d); 4.43-4.40 (1 H, m); 3.60-3.50 (1H, m); 2.85-2.58 (2H, m); 1.82-1.60 (2H, m); 1.21 (3 H, d).

(1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide

MS (APCI) 431 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.46 (1 H, d); 8.43 (1 H, d); 8.04 (1H, doublet of single); 7.71-7.68 (1 H, m); 7.54 (1 H, dt); 7.55 (2H, d); 7.28-7.21 (2H, m); 6.95 (2H, d); 5.32 (2H, s); 4.40-4.30 (1 H, m); 3.87-3.83 (1 H, m); 2.98-2.93 (1 H, m); 2.79-2.70 (1 H, m); 2.34 (1 H, broad singlet); 1.92-1.80 (2H, m); 1.31 (3 H, d).

Example 36

(1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.4 g, Example 33), 3-cyano-4-fluorobromobenzene (0.399 g), ethanol (10 ml), 2M aqueous sodium carbonate solution (1.66 ml) and tetrakis (triphenylphosphine) palladium (0) (0.3 g) were heated at 80 ° C. for 3 hours to describe the method described in Example 12b. It was prepared according to. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a solid (0.24 g).

m.p. 108-109 ℃

MS (APCI) 377 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.55 (1 H, s); 8.45 (1 H, d); 7.75-7.70 (2H, m); 7.60-7.50 (1 H, m); 7.45-7.40 (2H, m); 7.25-7.20 (2H, m); 6.95 (2H, d); 4.45-4.35 (1 H, m); 3.90-3.80 (1 H, m); 3.00-2.90 (1 H, m); 2.80-2.70 (1 H, m); 2.15 (1 H, d); 1.90-1.80 (2H, m); 1.30 (3 H, d).

Example 37

(1S, 2R) -2,5-Difluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide.

a) 4-bromo-2,5-difluorobenzenesulfonamide.

Ammonium hydroxide (5 ml) was added to 2,5-difluoro-4-bromophenylsulfonyl chloride (4.3 g) in tetrahydrofuran (20 ml) at room temperature (caution: exotherm) and stirred for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. Ethyl acetate was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and the residue triturated with 20% diethyl ether in isohexane to give the subtitle compound as a solid (4.3 g).

m.p. 161-163 ℃

MS (EI) 271/273 (M ⁺ )

¹ H NMR (CDCl ₃ ) 7.69 (1H, t); 7.50 (1 H, dd); 5.17 (2H, s);

b) (1S, 2R) -2,5-difluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.4 g, Example 33), 4-bromo-2,5-difluoro From robenzenesulfonamide (0.19 g, Example 37a), ethanol (3 ml), 2M aqueous sodium carbonate solution (0.7 ml), and tetrakis (triphenylphosphine) palladium (0) (0.03 g) at 80 ° C. for 3 hours. Prepared according to the method described in Example 12 by heating. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a foam (0.11 g).

MS (APCI) 449 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1 H, d); 7.69 (1 H, dd); 7.54 (1 H, dd); 7.48 (2H, doublet); 7.31-7.02 (2H, doublet); 6.97 (2H, doublet); 5.16 (2H, s); 4.44-4.39 (1 H, m); 3.88-3.85 (1 H, m); 2.99-2.92 (1 H, m); 2.80-2.74 (1 H, m); 2.12 (1 H, d); 1.92-1.80 (2H, m); 1.32 (3H, d).

Example 38

(1S, 2R) -3-chloro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-carbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-chlorobenzonitrile ( 0.288 g), 2M aqueous sodium carbonate solution (0.76 ml), and tetrakis (triphenylphosphine) palladium (0) (0.075 g) in ethanol (5 ml) were heated at 90 ° C. for 4 hours to describe the method described in Example 12b. It was prepared according to. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.18 g).

MS (APCI) 393 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1H, doublet); 7.69-7.67 (2H, m); 7.56-7.54 (1 H, m); 7.54-7.52 (1 H, m); 7.51 (2H, d); 7.49-7.22 (1 H, m); 6.98 (2H, d); 4.41-4.39 (1 H, m); 3.86-3.85 (1 H, m); 2.95-2.94 (1 H, m); 2.76-2.73 (1 H, m); 2.25-2.24 (1 H, m); 1.89-1.84 (2H, m); 1.32 (3H, d).

Example 40

(1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) naphthalen-2-yl] -N, N-dimethylacrylamide.

a) (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) naphthalen-2-yl] -N, N-dimethylacrylamide.

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.25 g, Example 10), N, N-dimethylacrylamide (0.64 g), tri-o-tolylphosphine (0.04 g), triethylamine (2 ml) and palladium acetate (0.01 g) are added to acetonitrile (10 ml), and the mixture is added to the test tube for 70 hours in a sealed test tube. Heated to ° C. The reaction mixture is left to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel) eluting with 20% acetone in isohexane and then 50% acetone in isohexane and finally 5% methanol in dichloromethane to give the subtitle compound as an oil. (0.27 g).

MS (APCI) 405 (M + H) ⁺

NMR (CDCl ₃ ) 8.52 (1H, s); 8.46 (1 H, d); 7.84 (1 H, s); 7.80 (1 H, d); 7.75 (1 H, s); 7.66 (2H, d); 7.56 (1 H, d); 7.25-7.20 (1 H, m); 7.14 (2H, d); 6.96 (1 H, d); 4.55-4.47 (1 H, m); 3.94-3. 88 (1 H, m); 3.21 (3H, s); 3.09 (3H, s); 3.02-2.92 (1 H, m); 2.80-2.70 (1 H, m); 1.93-1.85 (2H, m); 1.36 (3 H, d).

b) (2S, 3R) -3- [6- (3-hydroxy) -5-pyridin-3-ylpent-2-yloxy) naph-2-yl] propionic acid, dimethylamide

A 10% palladium slurry on carbon (0.1 g) in ethanol (20 ml) was added to (2S, 3R) -3- [6- (3-hydroxy) -5-pyridin-3-ylpent-2- in ethanol (30 ml). Iloxy) naphth-2-yl] propenoic acid, dimethylamide (0.27 g, Example 40a) was added and the mixture was hydrogenated at 1.5 atmospheres for 2 hours. This reaction mixture was purified by Celite The catalyst was removed by filtration through, and the filter cake was washed with ethanol (2 x 50 ml). The combined filtrate and wash were concentrated under reduced pressure and the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give the title compound as an oil (0.11 g).

MS (APCI) 407 (M + H) ⁺

NMR (CDCl ₃ ) 8.52 (1H, s); 8.46 (1 H, d); 7.69 (1 H, d); 7.63 (1 H, d); 7.59-7.55 (2H, m); 7.33 (1 H, dd); 7.24-7. 22 (1 H, m); 7.11-7.09 (2H, m); 4.52-4.45 (1 H, m); 3.97-3.90 (1 H, m); 3.10 (1 H, t); 2.94 (6H, d); 2.76-2.66 (4H, m); 2.35-2.15 (2H, m); 1.95-1.85 (2H, m); 1.34 (3 H, d).

Example 41

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-N-sulfonamido-N'-isopropyl-urea.

a) N-[(methylamino) carbonyl], 3-bromobenzenesulfonamide

Isopropyl isocyanate (0.6 ml) was added to a solution of 3-bromobenzenesulfonamide (1.18 g) and copper (I) (0.025 g) in anhydrous dimethylformamide (3 ml). The resulting solution was stirred for 20 hours, poured into 2M hydrochloric acid solution (50 ml) and the resulting precipitate was filtered off. The resulting solid was dissolved in dichloromethane (40 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with hexane and filtered to give the subtitle compound as a solid (1.34 g).

m.p. 136.5-137 ℃

MS (APCI) 321,323 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.18 (1 H, br); 8.04 (1H, t); 7.82 (1 H, dt); 7.76 (1 H, dt); 7.42 (1 H, t); 6.38 (1 H, d); 4.01-3.88 (1 H, m); 1.18 (6H, d)

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-oxy) biphenyl-3-N-sulfonamido-N'-isopropyl-urea.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 11), N-[( Methylamino) carbonyl], 3-bromobenzenesulfonamide (0.28 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.05) in toluene (5 ml) and ethanol (2 ml) from g) according to the method described in example 4e. The reaction was heated at 120 ° C. for 4 hours. After cooling 2M hydrochloric acid (10 ml) and methanol were added. The mixture was stirred for 30 minutes and extracted with ether (30 ml). The remaining aqueous layer was adjusted to pH 7 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml) and tetrabutylammonium fluoride solution (1M, 10 ml) in tetrahydrofuran was added. This solution was stirred for 18 hours and then concentrated under reduced pressure. The residue was partitioned between pH 7 buffer and ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford a gum (0.07 g). This was triturated with isohexane: ether (9: 1) to give a solid.

MS (APCI) 498 (M + H) ⁺

¹ H NMR (DMSO) 8.45 (1 H, s); 8.39 (1 H, d); 8.07 (1 H, s); 7.87 (1 H, d); 7.79 (1 H, d); 7.7-7.5 (4 H, m); 7.35-7.25 (1 H, m); 7.05 (2H, d); 6.33 (1 H, br s); 5.05-4.95 (1 H, m); 4.40-4.30 (1 H, m); 3.70-3.50 (2H, m); 2.90-2.55 (3H, m); 1.95-1.80 (1 H, m); 1.80-1.55 (1 H, m); 1.25 (3H, d); 0.98 (6 H, d).

Example 42

(1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1-morpholin-4-yl-propane -1-one, oxalate.

a) 1-morpholin-4-yl-propenone.

Acryloyl chloride (8 g), morpholine (7.7 g) and triethylamine (8.94 g) were added to tetrahydrofuran (100 ml) at -30 ° C. The reaction mixture was stirred and allowed to slowly reach room temperature overnight. Precipitated triethylamine hydrochloride was removed by filtration and the filtrate was concentrated under reduced pressure. The residue thus obtained was stirred in a 1: 1 mixture of isohexane: diethyl ether (500 ml) to precipitate more triethylamine hydrochloride. This salt was filtered off and the filtrate was concentrated under reduced pressure to give a subtitle compound as an oil (11 g).

GC / MS 141 (M) ⁺

NMR (CDCl ₃ ) 6.55 (1H, dd); 6.32 (1H, doublet); 5.72 (1H, doublet); 3.70 (8H, broad singlet).

b) (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1-morpholin-4-yl -Propenone.

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.60 g, Example 10), 1-morpholin-4- Example 40a is described from triethylamine (2 ml) in mono-propenone (1.09 g, Example 42a), palladium acetate (0.03 g), tri-O-tolylphosphine (0.09 g) and acetonitrile (10 ml). It was prepared according to the method described. After completion of the reaction, the crude material was eluted with 20% acetone in isohexane, then purified by flash column chromatography (silica) eluting with 50% acetone in isohexane and finally with 5% methanol in dichloromethane. The subtitle compound was obtained as a foam (0.52 g).

MS (APCI) 447 (M + H) ⁺

NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1H, doublet); 7.85 (1 H, d); 7.79 (1 H, d); 7.72 (1 H, d); 7.66 (1 H, s); 7.64 (1 H, dd); 7.56 (1 H, dd); 7.26-7.20 (1 H, m); 7.15 (1 H, dd); 7.12 (1 H, dd); 6.91 (1 H, d); 4.53-4.49 (1 H, m); 3.91 (1 H, br. S); 3.74 (8H, br. S); 2.99-2.92 (1 H, m); 2.80-2.73 (1 H, m); 2.30 (1 H, br. S); 1.93-1.85 (2H, m); 1.36 (3 H, d).

c) (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1-morpholin-4-yl -Propan-1-one, oxalate.

(1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1-morpholin-4-yl-pro Prepared according to the method described in Example 40b from phenone (0.52 g, Example 42b), 10% palladium on carbon (0.2 g) and ethanol (50 ml). After completion of the reaction, the crude material was purified by flash column chromatography (silica) eluting with 5% ethanol in dichloromethane to give an oil (0.5 g). A portion of this (0.15 g) was treated with an ether solution of oxalic acid to give the title compound as a solid (0.14 g).

m.p. 156-159 ℃

MS (APCI) 449 (M + H) ⁺

NMR (DMSO) 8.47 (1 H, d); 8.41 (1 H, dd); 7.72-7.67 (3H, m); 7.62 (1 H, s); 7.36-7.32 (2H, m); 7.24 (1 H, d); 7.11 (1 H, dd); 4.45-4.39 (1 H, m); 3.62-3.56 (1 H, m); 3.50-3.37 (8H, m); 2.93 (2H, t); 2.83-2.79 (1 H, m); 2.73-2.69 (3H, m); 1.92-1.88 (1 H, m); 1.71-1.66 (1H, m); 1.28 (3 H, d).

Example 43

(3R, 4S) -4- [6- (3-Morpholin-4-yl-propyl) naphthalen-2-yloxy] -1-pyridin-3-yl-pentan-3-ol, oxalic acid salt.

Diborane (1.0 M solution in tetrahydrofuran, 10 ml) was cooled to 0 ° C. and stirred under nitrogen atmosphere. To (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1 in tetrahydrofuran (10 ml) Morpholin-4-yl-propan-1-one, oxalic acid salt (0.35 g, Example 42c) was added dropwise over a period of 15 minutes. The resulting colorless solution was raised to reflux and heated at reflux for 1 h. The reaction was left to cool to room temperature, acidified with 6M hydrochloric acid (2 ml) and heated at reflux for 0.5 h. The solution was cooled and then partitioned between ether and water. The aqueous layer was basified with 2M sodium hydroxide and extracted with ethyl acetate. This ethyl acetate was washed with brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed by evaporation under reduced pressure and the residue was purified by silica flash column chromatography eluting with dichloromethane containing 2% triethylamine and 1% ethanol to give the free base of the title compound as an oil (0.25 g). ). This was treated with oxalic acid ether solution to give the title compound as a solid (0.15 g).

MS (APCI) 435 (M + H) ⁺

NMR (DMSO) 8.44 (1 H, d); 8.38 (1 H, dd); 7.73 (2H, doublet); 7.64 (2H, doublet); 7.35-7. 26 (3H, m); 7.12 (1 H, dd); 4.43-4.39 (1 H, m); 3.78 (4H, br. S); 3.60-3.58 (1 H, m); 3.42-3.35 (2H, m); 3.13 (4H, br. S); 3.02 (1 H, t); 2.82-2.66 (3H, m); 2.09-1.95 (2H, m); 1.95-1.82 (1 H, m); 1.76-1.62 (1 H, m); 1.28 (3 H, d).

Example 44

(3R, 4S) -4- [6- (3-Methylaminopropyl) naphthalen-2-yloxy] -1-pyridin-3-yl-pentan-3-ol, oxalic acid salt.

(1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N-methylpropion in tetrahydrofuran (30 ml) Prepared according to the method described in Example 43 from amide (0.12 g, Example 85c) and diborane (10 ml of 1.0M solution in tetrahydrofuran). After completion of the reaction, the solvent was removed by evaporation under reduced pressure and the residue was treated with oxalic acid ether solution to give the title compound as a hygroscopic solid (0.017 g).

MS (APCI) 379 (M + H) ⁺

NMR (DMSO) 8.67 (1 H, br.s); 8.44 (1 H, d); 8.38 (1 H, dd); 7.73 (2H, doublet); 7.63 (2H, m); 7.33-7.26 (3H, m); 7.12 (1 H, dd); 4.43-4.40 (1 H, m); 3.62-3. 57 (1 H, m); 2.95-2.60 (6H, m); 2.54 (3H, s); 2.60-1.85 (3H, m); 1.72-1.63 (1 H, m); 1.28 (3 H, d).

Example 45

(1S, 2R) -4 '-(2-hydroxy-1-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile.

3-cyanobenzeneboronic acid (0.40 g), (3S, 4R) -3- (4-bromophenyloxy) -2-methyl-6- (3-pyridyl) hexan-4-ol (0.90 g, Example 61d), 2M aqueous sodium carbonate solution (2.72 ml) and tetrakis (triphenylphosphine) palladium (0) (0.160 g) in ethanol (4 ml) were prepared according to the method described in Example 12b. The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a gum (0.54 g).

MS (APCI) 387 (M + H) ⁺

¹ H NMR (DMSO) 8.35 (2H, s); 8.07 (1 H, s); 7.95 (1 H, d); 7.75 (1 H, d); 7.69-7.5 (4 H, m); 7.25 (1 H, t); 7.1 (2H, d); 5.0 (1H, d); 4.2-4.12 (1 H, m); 3.7-3.6 (1 H, m); 2.85-2.72 (1 H, m); 2.7-2.65 (1 H, m); 2.2-2.05 (1 H, m); 1,85-1.55 (2H, m); 0.9 (6H, dd).

Example 46

(3R, 4S) -1-pyridin-3-yl-4- [4 '-(2-pyrrolidin-1-yl-ethoxy) biphenyl-4-yloxy] pentan-3-ol.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.190 g, Example 33), 1- [2 in ethanol (2 ml) Method described in Example 12b from (4-bromophenoxy) ethyl] pyrrolidine (0.27 g), 2M aqueous sodium carbonate solution (0.75 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) It was prepared according to. The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil which crystallized under high vacuum for 24 hours. Triturate with diethyl ether to isolate the title compound as a foam (0.194 g).

MS (APCI) 447.2 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1H, doublet); 7.55 (1 H, dt); 7.46 (4H, d); 7.22 (1H, doublet); 6.98 (2H, d); 6.92 (2H, d); 4.37 (1 H, dt); 4.15 (2H, t); 3.88-3.85 (1 H, m); 2.83 (3H, t); 2.78-2.67 (1 H, m); 2.73-2.63 (4H, m); 2.2 (1H, br) 1.89-1.80 (6H, m); 1.30 (3 H, d).

Example 47

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -4- (2-morpholin-4-yl-ethoxy) biphenyl-3-carbo Nitrile.

a) 5-bromo-2- (2-morpholin-4-yl-ethylamino) benzonitrile.

5-bromo-2-fluorobenzonitrile (1.0 g) and 4- (2-aminoethyl) morpholine (0.65 g) were mixed together in acetonitrile (5 ml) at 70 ° C. for 4 hours, cooled to carbonated Poured into aqueous sodium hydrogen solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with 2.5% methanol in dichloromethane containing 1% triethylamine to give the subtitle compound as an oil (0.77 g).

MS (APCI) 310,312 (M + H) ⁺

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -4- (2-morpholin-4-yl-ethoxy) biphenyl-3 Carbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.190 g, Example 33), 5-bromo-2- (2-mol From phosphorin-4-yl-ethylamino) benzonitrile (0.31 g, Example 47a), 2M aqueous sodium carbonate solution (0.75 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (2 ml) Prepared according to the method described in Example 12b. The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil which crystallized under high vacuum for 24 hours. Triturate with diethyl ether to isolate the title compound as a foam (0.19 g).

MS (APCI) 487.2 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1H, d); 8.45 (1 H, dd); 7.60-7.54 (3H, m); 7.40 (2H, doublet); 7.24-7.22 (1H, dd); 6.93 (2H, doublet); 6.70 (1 H, d); 5.40 (1 H, t); 4.38-4.35 (1 H, m); 3.87-3.83 (1 H, m); 3.76 (4H, doublet); 3.27 (2H, q); 2.95-2.90 (1 H, m); 2.80-2.75 (1 H, m); 2.70 (2H, t); 2.54-2.49 (4H, m); 2.20 (1 H, d); 1.89-1.80 (2H, m); 1.30 (3 H, d).

Example 48

(3R, 4S) -4- (3'-Methanesulfonylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol.

a) 1-bromo-3-methanesulfonylbenzene

3-bromothioanisole was dissolved in methanol (20 ml) and cooled to 0 ° C. (ice / water bath). Oxone A solution of (9.22 g) in water (30 ml) was added thereto and the resulting opaque slurry was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and the product extracted with dichloromethane. The combined dichloromethane fractions were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed by evaporation under reduced pressure to obtain a subtitle compound as a solid (1.02 g).

m.p. 63-64 ℃

GC / MS 236/238 (M ⁺ )

¹ H NMR (CDCl ₃ ) 8.10 (1 H, s); 7.89 (1 H, dd); 7.80 (1 H, dd); 7.47 (1 H, t); 3.08 (3H, s).

b) (2S, 3R) -2- [4- (3'-methylsulfonyl) biphenyloxy] -5- (pyridin-3-yl) pentan-3-ol.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.2 g, Example 11), 1- Bromo-3-methanesulfonylbenzene (0.23 g, Example 48a), ethanol (2 ml), toluene (5 ml), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03) from g) at reflux for 4 h to prepare according to the method described in Example 12b. After cooling, the solution was concentrated under reduced pressure. Conc. Hydrochloric acid (1 ml) was added to the solution in methanol (5 ml) and the suspension was stirred at room temperature for 1 hour. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give the title compound as an oil (0.17 g).

MS (APCI) 412 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, br.s); 8.47 (1 H, br. S); 8.11 (1 H, t); 7.89-7. 80 (2H, m); 7.63 (1 H, d); 7.59-7.52 (3H, m); 7.26-7.21 (1 H, m); 6.98 (2H, doublet); 4.43-4.39 (1 H, m); 3.92-3.83 (1 H, m); 3.09 (3H, s); 2.96 (1 H, m); 2.77-2.70 (1 H, m); 2.25 (1 H, br. S); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 49

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carboxylic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 3-bromo-2-benzamide (0.20 g), 2M aqueous sodium carbonate solution (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in ethanol (3 ml) were heated at 90 ° C. for 2 hours to describe the method described in Example 12b. It was prepared according to. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give the title compound as a solid (0.107 g).

m.p. 74-76 ℃

MS (APCI) 377 (M + H) ⁺

¹ H NMR (DMSO) 8.45 (1 H, s); 8.40 (1 H, d); 8.11 (2H, s); 7.80 (1 H, d); 7.75 (1 H, d); 7.64 (3H, d); 7.50 (1 H, t); 7.42 (1 H, s); 7.30 (1 H, t); 7.02 (2H, d); 5.31 (1 H, d); 5.02 (1 H, t); 3.57 (1 H, bs); 2.85-2.79 (1 H, m); 2.70-2.62 (1 H, m); 1.89-1.85 (1 H, m); 1.70-1.65 (1 H, m); 1.25 (3 H, d).

Example 50

(1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-yloxy] -acetamide.

a) 2- (3-bromophenoxy) -acetamide.

A mixture of 2-chloroacetamide (5.6 g), 3-bromophenol (10 g), potassium carbonate (8.3 g) and potassium iodide (1 g) in acetonitrile was stirred at room temperature for 72 hours. The resulting mixture was filtered and the solid was washed with ethyl acetate and then water. The dried solid was recrystallized from boiling ethanol: water (8: 2) to give a subtitle compound as a solid (13.8 g).

m.p. 96-98 ℃

MS (APCI) 228 (M + H) ⁺

¹ H NMR (DMSO) 7.55 (1 H, br.s); 7.4 (1 H, br. S); 7.25 (1 H, t); 7.13-7.18 (2H, m); 6.96 (1 H, dd); 4.45 (2H, s).

b) (2S, 3R) -3- {4- [3-hydroxy-5- (3-pyridyl) pentan-2-yloxy] phenyl} phenyloxyacetic acid, amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 2- (3-bromophenoxy) acet Prepared according to the method described in Example 12b from amide (0.23 g), 2M aqueous sodium carbonate solution (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a colorless solid, which was then boiled with ethyl acetate: isohexane (1: Recrystallization from 1) gave the title compound as a solid (0.138 g).

m.p. 120-122 ℃

MS (APCI) 407 (M + H) ⁺

¹ H NMR (DMSO) 8.15 (1 H, s); 8.46 (1 H, d); 7.56 (1 H, d); 7.49 (2H, d); 7.37 (1 H, t); 7.3-7.19 (2H, m); 7.1 (1H, s); 6.95 (2H, d); 6.86 (1H, doublet); 6.58 (1 H, br. S); 5.69 (1 H, br. S); 4.56 (2H, s); 4.45-4.35 (1 H, m); 3.9-3.85 (1 H, m); 3.0-2.9 (1 H, m); 2.8-2.7 (1 H, m); 2.26 (1 H, br. S); 1.9-1.8 (2H, m); 1.31 (3 H, d).

Example 51

(2S, 3R) -1-pyridin-3-yl-4- (2'-trifluoromethoxybiphenyl-4-yloxy) pentan-3-ol.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 2-bromo (trifluoromethyloxy) Prepared according to the method described in Example 12b from tetrakis (triphenylphosphine) palladium (0) (0.025 g) in benzene (0.26 g), 2M aqueous sodium carbonate solution (0.50 ml) and ethanol (3 ml). The reaction mixture was heated at 80 ° C. for 2 hours in a sealed vial. After cooling, the solution was concentrated under reduced pressure, taken up in acetone and filtered through a small plug of silica. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil (0.145 g).

MS (APCI) 418 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1H, doublet); 7.56 (1 H, dd); 7.43-7.30 (6H, m); 7.25-7.20 (1 H, m); 6.93 (2H, d); 4.45-4.35 (1 H, m); 3.93-3. 85 (1 H, m); 3.0-2.9 (1 H, m); 2.8-2.7 (1 H, m); 2.20 (1 H, br. S); 1.95-1.8 (2H, m); 1.32 (3H, d).

Example 52

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -6-methoxybiphenyl-3-carbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33), 3-bromo-4-methoxybenzonitrile (0.20 g), 2 M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) in toluene (5 ml) and ethanol (2 ml) were heated at 90 ° C. for 4 hours to give Example 12b It was prepared according to the method described in. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.17 g).

MS (APCI) 389/390 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, s); 8.46 (1 H, d); 7.60 (1 H, d); 7.56 (2H, m); 7.40 (2H, d); 7.23 (H, dd); 7.00 (1 H, d); 6.93 (2H, d); 4.39 (1 H, m); 3.87 (4H, m); 2.95 (1 H, m); 2.74 (1 H, m); 2.29 (1 H, br. S); 1.86 (2H, m); 1.32 (3H, d).

Example 53

(3R, 4S) -4- (4'-Chloro-2'-methoxy-5'-methylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), 5-bromo-2-chloro-4- Description of Example 12b by heating from methoxytoluene (0.12 g), 2M aqueous sodium carbonate solution (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.014 g) in ethanol (5 ml) at 90 ° C. for 4 hours. It was prepared according to the method described. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.13 g).

MS (APCI) 412 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.45 (1 H, dd); 7.57-7.54 (1 H, m); 7.46 (2H, d); 7.24-7. 21 (1 H, m); 7.12 (1 H, s); 6.95 (1 H, s); 6.90 (2H, d); 4.38-4.36 (1 H, m); 3.87-3. 85 (1 H, m); 3.78 (3H, s); 2.98-2.91 (1 H, m); 2.77-2.69 (1 H, m); 2.33 (3H, s); 2.19 (1 H, d); 1.87-1. 81 (2H, m); 1.31 (3 H, d).

Example 54

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid methylamide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 3-bromo-N-methylbenzamide ( From J. of Org.Chem., 1963, 28, 3147-3149) (0.214 g), 2M aqueous sodium carbonate solution (0.25 ml) and tetrakis (triphenylphosphine) palladium (0) (0.005 g) in ethanol (3 ml) Prepared according to the method described in Example 12b. The reaction mixture was heated at 80 ° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane. The product was further purified by flash column chromatography eluting with ethyl acetate to give the title compound as a solid (0.12 g).

m.p. 54-55 ℃

MS (APCI) 391 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1H, d); 8.45 (1 H, dd); 7.96-7.95 (1 H, m); 7.65 (2H, doublet); 7.57-7. 51 (3H, m); 7.46 (1 H, t); 7.24-7. 21 (1 H, m); 6.95 (2H, doublet); 6.26 (1 H, bs); 4.40-4.38 (1 H, m); 3.88-3.85 (1 H, m); 3.05 (3H, d); 2.95-2.92 (1 H, m); 2.78-2.72 (1 H, m); 2.32 (1 H, d); 1.89-1.83 (2H, m); 1.32 (3H, d).

Example 55

(1S, 2R)-[4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] acetic acid.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.6 g, Example 33), 4-bromophenylacetic acid (0.624 g ), Tetrakis (triphenylpropine) palladium (0) (0.5 g) in 2M aqueous sodium carbonate solution (2.5 ml) and ethanol (15 ml) according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. Water was added to the residue and washed with diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid and washed with diethyl ether. The aqueous layer was neutralized to pH 7.11 and the filtered solid was washed with diethyl ether to give the title compound as a solid (0.431 g).

m.p. 196-197 ℃

MS (APCI) 392 (M + H) ⁺

¹ H NMR (DMSO) 8.45 (1 H, d); 8.40 (1 H, d); 7.63 (1 H, dt); 7.55-7.52 (4H, m); 7.31-7.28 (3H, m); 6.99 (2H, doublet); 5.0 (1 H, bs); 4.33-4.30 (1 H, m); 3.58-3.37 (3H, m); 2.80-2.77 (1 H, m); 2.67-2.63 (1 H, m); 1.88-1.85 (1 H, m); 1.66-1.62 (1 H, m); 1.24 (3 H, d).

Example 56

(1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-2-yl] acetamide .

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), 2-bromo-4- (tri Fluoromethyl) acetanilide (0.28 g), 2 M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.014 g) in ethanol (5 ml) were heated at reflux for 2 hours. Prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-5% ethanol gradient in dichloromethane to give the title compound as a solid (0.16 g).

m.p. 44-47 ℃

MS (APCI) 459 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.47 (1H, d); 8.44 (1 H, dd); 7.60-7.56 (2H, m); 7.45-7.41 (2H, m); 7.29-7.21 (3H, m); 6.99 (2H, d); 4.40-4.39 (1 H, m); 3.90-3.86 (1 H, m); 2.98-2. 81 (1 H, m); 2.78-2.71 (1 H, m); 2.64 (1 H, br. S); 2.06 (3H, s); 1.89-1.87 (3H, m); 1.35 (3 H, d).

Example 57

(1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-2-yl] -N-methylacetamide

a) 2- (2-bromo-phenyl) -N-methylacetamide.

To a solution of 2-bromophenyl acetic acid (2.15 g) in dichloromethane (100 ml) methylamine (2M solution in tetrahydrofuran, 6 ml), 4-dimethylaminopyridine (1.32 g) and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.055 g) was added. After the mixture was stirred at room temperature for 16 hours, the organic portion was washed with 2M aqueous hydrochloric acid solution, dried over magnesium sulfate and filtered. The filtrate was concentrated to give a solid (2.04 g).

MS (APCI) 228/230 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 7.60 (1H, d); 7.33 (2 H, m); 7.17 (1 H, t); 5.40 (1 H, s); 3.72 (2H, s); 2.79 (3H, d).

b) (2S, 3R) -5- (3-pyridyl) -2- [4- (2 (2-N-methylethanamide) phenyl) phenoxy] pentan-3-ol

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 2- (2-bromophenyl) -N-methylacetamide (0.228 g), 2 M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) dissolved in ethanol (3 ml) were heated at 90 ° C. for 90 minutes. Prepared according to the method described in Example 12b. After cooling, the solution is concentrated and azeotrope twice more with ethanol. The residue was triturated with acetone and filtered through silica gel. The filtrate was concentrated, dissolved in dichloromethane and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a solid (0.055 g).

m.p. 85-86 ℃

MS (APCI) 405 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.45 (2H, d); 7.58 (1 H, d); 7.34-7.15 (7H, m); 6.92 (2H, d); 5.37 (1 H, s); 4.35 (1 H, t); 3.84 (1 H, t); 3.54 (2H, s); 2.93 (1 H, m); 2.76 (4H, m); 1.87 (3 H, m); 1.33 (3 H, d).

Example 58

(1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methylbiphenyl-4-yl] acetamide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 4-bromo-3-methylacet Heated at 90 ° C. for 2 hours from anilide (0.228 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) in ethanol (3 ml) described in Example 12b. It was prepared according to the method. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane and then reversed phase HPLC eluting with a 25-100% acetonitrile gradient in 0.1 w / v aqueous ammonium acetate solution. Purification with water gave the title compound as an oil (0.041 g).

MS (APCI) 405 (M + H) ⁺

¹ H NMR (DMSO) 9.9 (1H, s); 8.45 (1 H, broad singlet); 8.39 (1 H, broad singlet); 7.64 (1 H, d); 7.46-7.43 (2H, m); 7.32-7.29 (1 H, t); 7.19 (2H, d); 7.08 (1 H, d); 6.94 (2H, d); 5.01 (1 H, d); 4.30 (1 H, t); 3.60-3.52 (1 H, m); 2.85-2.79 (1 H, m); 2.71-2.63 (1 H, m); 2.20 (3H, s); 2.05 (3H, s); 1.89-1.85 (1 H, m); 1.71-1.66 (1H, m); 1.24 (3 H, d).

Example 59

(1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] -methanesulfonamide

a) 3-bromomethanesulfonanilide

Triethylamine (0.6 ml) was added to a stirred solution of 3-bromoaniline (0.5 ml) in dichloromethane (10 ml). The resulting mixture was stirred at room temperature for 15 minutes, and then methanesulfonyl chloride (0.36 ml) in dichloromethane (5 ml) was added dropwise. The reaction mixture was stirred at rt for 3 h. Water was added and the product extracted with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane and then methanol to give the subtitle compound as a solid (0.662 g).

m.p. 109 ℃

¹ H NMR (DMSO) 9.99 (1H, br.s); 7.37 (1 H, s); 7.31-7.26 (2H, m); 7.24-7. 15 (1 H, m); 3.04 (3H, s).

b) (1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] -methanesulfonamide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 3-bromomethane sulfonanilide (0.250 g), tetrakis (triphenylphosphine) palladium (0) (0.020 g) dissolved in 2M aqueous sodium carbonate solution (0.50 ml) and ethanol (3 ml) and heated at 90 ° C. for 2 hours in the method described in Example 12b. Prepared accordingly. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane and then reversed phase HPLC eluting with a 25-100% acetonitrile gradient in 0.1 w / v aqueous ammonium acetate solution. Purification with water gave the title compound as an oil (0.060 g).

MS (APCI) 427 (M + H) ⁺

¹ H NMR (DMSO) 9.82 (1 H, br.s); 8.45 (1 H, s); 8.40 (1 H, d); 7.64 (1 H, d); 7.50 (2H, d); 7.41-7.31 (4H, m); 7.14 (1 H, d); 7.01 (2H, d); 5.01 (1 H, d); 4.37-4.31 (1 H, m); 3.61-3.52 (1 H, m); 3.02 (3H, s); 2.87-2.78 (1 H, m); 2.70-2.62 (1 H, m); 1.91-1.82 (1 H, m); 1.71-1.62 (1H, m); 1.24 (3 H, d).

Example 60

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.30 g, Example 33), 4-bromophenylsulfonic acidamide (0.26 g), ethanol (6 ml), 2M aqueous sodium carbonate solution (1.0 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) were heated at 90 ° C. for 6 hours to describe the method described in Example 12b. It was prepared according to. After completion of the reaction, the residue was purified by silica gel column chromatography eluting with methanol: ethyl acetate (5:95) to afford the title compound as a solid (0.04 g).

m.p. 222-223 ℃

MS (APCI) 413/414 (MH) ^-

NMR (DMSO) 8.44 (1 H, s); 8.39 (1 H, d); 7.81 (4H, q); 7.64 (2H, d); 7.36 (2H, br. S); 7.30 (1 H, dd); 7.04 (2H, d); 5.01 (1 H, d); 4.36 (1 H, m); 3.55 (1 H, m); 2.82 (1 H, m); 2.65 (1 H, m); 1.88 (1 H, m); 1.66 (1 H, m); 1.24 (3 H, d).

Example 61

(1S, 2R) -4 '-(2-hydroxy-1-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acidamide

a) (2S) -2- (4-bromophenoxy) -3-methylbutanoic acid, methyl ester

Diethylazodicarboxylate (17.5 ml) in toluene (60 ml) anhydrous, triphenylphosphine (34 g), methyl (R) -2-hydroxy-3-methylbutanoate (17 g) in anhydrous toluene (180 ml) , J. Am. Chem. Soc., (1990), 112, 21, 7659) and 4-bromophenol (24 g) were added dropwise over 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and concentrated to about half of the original volume under reduced pressure. Isohexane (700 ml) mixture was added and the mixture was stirred at room temperature for 20 minutes. The solution was filtered to remove triphenylphosphine oxide, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with isohexane: dichloromethane (1: 4) followed by (2: 3) to give the subtitle compound as an oil (28 g).

¹ H NMR (CDCl ₃ ) 7.36 (2H, d); 6.76 (2H, d); 4.33 (1 H, d); 3.74 (3H, s); 2.35-2.2 (1H, m); 1.06 (6H, t)

b) (2S) -2- (4-bromophenoxy) -3-methyl-1-butanol

Solid sodium borohydride (11.8 g) was cooled in a stirred solution of (2S) -2- (4-bromophenoxy) -3-methylbutanoic acid, methyl ester (27.7 g) in ethanol (400 ml), 3 Add in 3 portions over days. The reaction was concentrated under reduced pressure and the residue partitioned between 2M hydrochloric acid (400 ml) and ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: isohexane (1: 1) to give a subtitle compound as an oil (13.7 g).

¹ H NMR (CDCl ₃ ) 7.37 (2H, d); 6.86 (2H, d); 4.15-4.05 (1 H, m); 3.85-3.75 (2H, m); 2.15-2.0 (1 H, m); 0.99 (3H, d); 0.96 (3H, d).

c) (3RS, 4S) -4- (4-bromophenoxy) -5- (methyl) -1- (pyridin-3-yl) -hex-1-yn-3-ol

Oxalyl chloride (6.0 ml) was added dropwise to a solution of dimethyl sulfoxide (7.5 ml) in anhydrous dichloromethane (300 ml) at −70 ° C. The resulting solution was stirred for 15 minutes, and then a solution of (2S) -2- (4-bromophenoxy) -3-methyl-1-butanol (13 g) in anhydrous dichloromethane (100 ml) was added at -70 ° C. Added dropwise. The mixture was further stirred for 15 minutes, then triethylamine (45 ml) was added. The mixture was allowed to stand at 10 ° C while stirring. The mixture was then diluted with isohexane (600 ml) and stirred for 10 minutes, filtered and concentrated under reduced pressure. The residue was dissolved in isohexane (500 ml) and ether (50 ml), refiltered and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (100 ml) and 1-rithio-2-pyridin-3-ylacetylene solution [n-butyllithium (2.5 M in hexane, 30 ml) at -78 ° C was added to tetrahydrofuran (150 ml To a solution of pyridin-3-ylacetylene (8.0 g) (J. Amer. Chem. Soc. The mixture was allowed to stand at room temperature for 30 minutes and poured into saturated aqueous ammonium chloride (200 ml) solution. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (20 g) was purified by silica column chromatography eluting with dichloromethane followed by dichloromethane: ethyl acetate (4: 1) to give the subtitle compound as an oil and as a 3: 1 mixture of diastereomers (15.9 g). .

MS (APCI) 360,362 (M + H) ⁺

d) (3RS, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol

(3RS, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-hex-1-yn-3-ol (13.6 g) in ethyl acetate (350 ml) And hydrogenated at 3 atmospheres over 6 days using 10% rhodium on activated carbon (2.1 g) as catalyst. The catalyst and solvent were replaced five times during this period. Celite this mixture Filtration through and the filtrate was concentrated under reduced pressure to give a. The mixture was purified by HPLC eluting with dichloromethane: 2-propanol (97: 3) to reduce and unreduced (6.0 g), pure (3S, 4S) -4- (4-bromophenoxy) -5. -(Methyl) -1-pyridin-3-yl-3-hexanol (1.73 g) and pure (3R, 4S) -4- (4-bromophenoxy) -5- (methyl) -1-pyridine- A mixed fraction containing 3-yl-3-hexanol (2.73 g) was obtained.

(3S, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol

¹ H NMR (CDCl ₃ ) 8.46-8.43 (2H, m); 7.48 (1 H, dt); 7.35 (2H, d); 7.20 (1 H, doublet); 6.84 (2H, d); 3.93 (1 H, dd); 3.85-3.75 (1 H, m); 2.95-2.83 (1 H, m); 2.78-2.65 (1 H, m); 2.15-2.05 (2H, m); 1.9-1.65 (2H, m); 0.95 (3H, d); 0.92 (3H, d).

(3R, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol

¹ H NMR (CDCl ₃ ) 8.48-8.43 (2H, m); 7.50 (1 H, dt); 7.35 (2H, d); 7.21 (1H, doublet); 6.86 (2H, d); 4.06 (1H, doublet); 3.90-3.75 (1 H, m); 2.95-2.85 (1 H, m); 2.75-2.63 (1 H, m); 2.1-1.95 (1 H, m); 1.95-1.75 (2H, m); 1.71 (1 H, d); 0.97 (3H, d); 0.89 (3H, d).

e) 3- [4- (4-bromophenoxy) -3- (tert-butyldimethylsilanyloxy) -5-methylhexyl] pyridine.

Solid tert-butyldimethylsilyl chloride (0.46 g) to (3R, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol (0.93 g) And anhydrous dimethylformamide (12 ml) solution of imidazole (0.26 g) and the resulting solution was stirred for 3 days at room temperature. Water (100 ml) and ether (100 ml) were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane followed by dichloromethane: hexanes (1: 1) to give a subtitle compound as an oil (0.70 g).

¹ H NMR (CDCl ₃ ) 8.43-8.40 (1H, m); 8.33 (1 H, d); 7.34 (2H, d); 7.32-7.28 (1 H, m); 7.16 (1 H, dd); 6.86 (2H, d); 4.03 (1H, t); 4.00-3.90 (1 H, m); 2.70-2.55 (2H, m); 2.15-2.05 (1 H, m); 1.95-1.75 (2H, m); 1.01 (3H, d); 0.99 (3H, d); 0.89 (9H, s); 0.08 (3H, s); 0.09 (3H, s).

f) (1S, 2R) -4 '-(2-hydroxy-1-isopropyl-4-pyridin-3-yl-butoxy) -biphenyl-3-sulphonic acid amide.

tert-butyllithium solution (1.7 M in pentane, 1.7 ml) was added to 3- [4- (4-bromophenoxy) -3- (tert-butyldimethylsilanyloxy) -5-methylhexyl at -78 ° C. ] Pridine (0.7 g, Example 61e) and tri-isopropyl borate (0.75 ml) were added dropwise over 5 minutes to a solution in tetrahydrofuran (20 ml). The solution was stirred for 30 minutes and then tert-butyllithium (0.5 ml) was added. The solution was further stirred for 30 minutes, then tert-butyllithium (0.5 ml) was added. After stirring for 30 minutes, saturated aqueous ammonium chloride solution (50 ml) was added followed by ethyl acetate (50 ml). The layers were separated, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ether to give the recovered starting material (0.29 g), which was then eluted with ethyl acetate: methanol (4: 1) (1S, 2R) -4 '-[2. -(tert-butyldimethylsilanyloxy) -1-isopropyl-4-pyridin-3-ylbutoxy] benzeneboronic acid was obtained. It was dissolved in toluene (5 ml) and ethanol (3.5 ml), and 3-bromobenzenesulfonamide (0.37 g), 2M aqueous sodium carbonate solution (2 ml) and tetrakis (triphenylphosphine) palladium (0) were added. The mixture was heated at 100 ° C. for 2 hours and left to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure and methanol (10 ml) and concentrated hydrochloric acid (2 ml) were added to the residue. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue and neutralized by the addition of solid sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (0.60 g) was purified by silica gel column chromatography eluting with dichloromethane followed by ether followed by ethyl acetate to give an oil (0.34 g). This was further purified by silica gel column chromatography eluting with dichloromethane: ethanol (19: 1). This material was then purified twice by reverse phase HPLC eluting with a 25-100% acetonitrile gradient in aqueous 0.1 w / v ammonium acetate solution. The material recovered in this purification was triturated with isohexane to give a solid (0.20 g).

MS (APCI) 441 (M + H) ⁺

¹ H NMR 8.37 (2H, s); 8.04 (1H, t); 7.83 (H, d); 7.73 (1 H, d); 7.65-7.5 (4 H, m); 7.37 (2H, s); 7.26 (1 H, dd); 7.12 (2H, d); 5.02 (1 H, d); 4.17 (1H, doublet); 3.7-3.55 (1 H, m); 2.85-2.7 (1 H, m); 2.7-2.55 (1 H, m); 2.25-2.05 (1 H, m); 1.9-1.7 (1 H, m); 1.7-1.5 (1 H, m); 0.95 (3H, d); 0.89 (3H, d).

Example 62

(1S, 2R)-[4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-yl] urea.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), 4-bromophenylurea (0.16 g ), 2M aqueous sodium carbonate solution (0.25 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in ethanol (3 ml) were prepared according to the method described in Example 12b. The reaction mixture was heated at 100 ° C. for 3 hours. After cooling, the solution was concentrated under reduced pressure. The residue was triturated with acetone and filtered through silica gel. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with 10% methanol in dichloromethane to afford the title compound as a solid (0.046 g).

m.p. 181-182 ℃

MS (APCI) 392 (M + H) ⁺

¹ H NMR (DMSO) 8.53 (1 H, s); 8.44 (1 H, s); 8.38 (1 H, d); 7.63 (1 H, d); 7.49-7.42 (6H, m); 7.31-7.27 (1 H, m); 6.95 (2H, d); 5.84 (2H, s); 5.0 (1 H, s); 4.31-4.27 (1 H, m); 3.55-3.53 (1 H, m); 2.86-2.59 (2H, m); 1.90-1.80 (1 H, m); 1.67-1.57 (1 H, m); 1.23 (3 H, d).

Example 63

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carboxylic acid (2-pyrrolidine -1-yl-ethyl) amide.

a) 4-bromo-3-methyl-N- (2-pyrrolidin-1-yl-ethyl) -benzamide

1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (2.68 g) to 4-bromo-3-methyl benzoic acid (3.0 g), 1- (2-aminoethyl) pi To 1-hydroxybenzotriazole hydrate (1.89 g) in rollidine (1.78 ml) and anhydrous N, N-dimethylformamide (30 ml). The reaction was stirred at rt for 24 h. This solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: methanol (9: 1) to give a subtitle compound as an oil (3.55 g).

MS (APCI) 313/315 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1 H, br.s); 7.73 (1 H, doublet); 7.44 (1 H, d); 7.30-7.22 (1 H, m); 3.86 (2H, q); 3.29 (2H, t); 3.27-3.23 (4H, m); 2.30 (3H, s); 2.05-1.98 (4H, m).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carboxylic acid (2-py Ralidin-1-yl-ethyl) -amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), 4-bromo-3-methyl- Tetrakis (triphenylphosphine) palladium in N- (2-pyrrolidin-1-yl-ethyl) benzamide (0.31 g, Example 63a), 2M aqueous sodium carbonate solution (0.57 ml) and ethanol (5 ml) Was prepared according to the method described in Example 12b by heating at reflux for 4 h). After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to give the title compound as an oil (0.14 g).

MS (APCI) 488 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.82 (1 H, br.t); 8.51 (1 H, d); 8.45 (1 H, dd); 8.0 (1H, s); 7.92 (1 H, d); 7.56 (1 H, d); 7.27 (1 H, s); 7.25-7. 22 (1 H, m); 7.21 (2H, d); 6.92 (2H, d); 4.42-4.39 (1 H, m); 3.93 (2H, q); 3.91-3.87 (1 H, m); 3.60 (4 H, m); 3.41 (2H, t); 3.01-2.93 (1 H, m); 2.78-2.70 (1 H, m); 2.50 (1 H, br.s); 2.27 (3H, s); 2.16 (4H, br.s); 1.91-1.83 (2H, m); 1.32 (3H, d).

Example 64

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) bimethyl-3-sulfonic acid (2,2,2-trifluoroethyl) amide.

a) (N-2,2,2-trifluoroethyl) -3-bromobenzenesulfonic acid amide.

3-bromobenzenesulphonic chloride (1.27 g) was stirred with 2,2,2-trifluoroethylamine hydrochloride (0.8 g) and triethylamine (1.7 ml) in tetrahydrofuran (30 ml). And the resulting mixture was stirred at rt for 20 h. The reaction mixture was concentrated and the residue was partitioned between ether (20 ml) and 2M hydrochloric acid (30 ml). Once the mixture was separated, the aqueous layer was extracted with ether and the combined extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane to give the subtitle compound as a solid (0.60 g).

m.p. 98-99 ℃

MS (GC) 317,319 (M) ⁺

¹ H NMR (CDCl ₃ ) 8.02 (1H, t); 7.81 (1 H, double doublet); 7.74 (1H, doublet); 7.42 (1 H, t); 4.95 (1 H, t); 3.71 (2H, m).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid (2,2,2-trifluoro Ethyl) amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), (N-2,2,2- Trifluoroethyl) -3-bromobenzenesulfonic acid amide (0.25 g, Example 64a), 2M aqueous sodium carbonate solution (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) in ethanol (5 ml) 0.014 g), and heated at 90 ° C. for 2 hours, according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to give the title compound as a solid (0.17 g).

m.p. 47-48 ℃

MS (APCI) 495 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.46 (1H, d); 8.42 (1 H, dd); 8.01 (1 H, s); 7.78-7.70 (2H, m); 7.58-7.49 (2H, m); 7.45 (2H, d); 7.26-7. 22 (1 H, m); 6.93 (2H, d); 4.41-4.29 (1 H, m); 3.86-3.80 (1 H, m); 3.70 (2H, q); 2.97-2.91 (1 H, m); 2.77-2.67 (1 H, m); 1.88-1.81 (2H, m); 1.30 (3 H, d).

Example 65

(1S, 2R) -1- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -biphenyl-4-yl] -3-methylurea

a) N- (4-bromophenyl) -N'-methyl urea

A methylamine solution (2M, 4 ml) in tetrahydrofuran was added to a solution of phenylisocyanate (1.06 g). Immediate precipitation of the product occurred. The reaction mixture was diluted with hexane (100 ml) and then filtered to give the subtitle compound as a foam (0.90 g).

MS (APCI) 229 (M + H) ⁺

¹ H NMR (DMSO) 8.63 (1 H, s); 7.37 (4H, s); 6.03 (1H, q); 2.62 (3 H, d).

b) (1S, 2R) -1- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -3-methylurea

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.149 g, Example 33), N- (4-bromophenyl) -N'-methyl urea (0.225 g), 2M aqueous sodium carbonate solution (1.0 ml) and tetrakis (triphenylphosphine) palladium (0) (0.028 g) in ethanol (3 ml) according to the method described in Example 12b. Prepared. The reaction mixture was heated at 100 ° C. for 2 hours in a sealed vial. After cooling, the solution was concentrated under reduced pressure. The residue was purified by silica chromatography eluting with tetrahydrofuran: hexanes (1: 1). The residue was further purified by silica gel chromatography eluting with dichloromethane: ethanol (9: 1), then the residue was further purified by reverse phase HPLC eluting with a 25-100% acetonitrile gradient in 0.1 w / v ammonium acetate aqueous solution. Purified. The HPLC fractions were concentrated under reduced pressure and the residue was taken up in ethanol, filtered and concentrated under reduced pressure to afford the title compound as a solid (0.050 g).

m.p. 139-141 ℃

MS (APCI) 406 (M + H) ⁺

¹ H NMR (DMSO) 8.54 (1 H, s); 8.44 (1 H, s) 8.39 (1 H, d); 7.63 (1 H, d); 7.49 (2H, d); 7.45 (4 H, s); 7.30 (1 H, t); 6.95 (2H, d); 6.01 (1 H, d); 4.98 (1 H, d); 4.29 (1 H, quintet); 3.6-3.5 (1 H, m); 2.85-2.75 (1 H, m); 2.7-2.6 (4H, m); 1.9-1.8 (1 H, m); 1.7-1.6 (1 H, m); 1.24 (3 H, s).

Example 66

(1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -N-isopropylacetamide.

(1S, 2R)-[4 ′-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetic acid (Example 55, 0.07 g ), Isopropylamine (0.012 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were added to dimethylformamide ( 2 ml) and stirred at room temperature for 16 hours. Dimethylformamide was removed by vacuum distillation and the residue was dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a solid (0.061 g). .

m.p. 103-104 ℃

MS (APCI) 433 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.47 (1 H, dd); 7.58-7.49 (5H, m); 7.30-7.26 (2H, m); 7.25-7.20 (1 H, m); 6.95 (2H, doublet); 5.2 (1H, br.s); 4.40-4.37 (1 H, m); 4.12-4.05 ((1H, m); 3.89-3.85 (1H, m); 3.56 (2H, s); 2.96-2.91 (1H, m); 2.76-2.71 (1H, m); 2.13 (1H, d) ; 1.90-1.81 (2H, m); 1.30 (3H, d); 1.10 (6H, d).

Example 67

(1S, 2R) -N-cyclopropyl-2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide.

Prepared according to the method described in Example 66. (1S, 2R)-[4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] acetic acid (Example 55, 0.07 g) , Cyclopropylamine (0.011g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.038g) and 1-hydroxybenzotriazole (0.027g) in dimethylformamide (2ml ) And stirred for 16 h at room temperature. Dimethylformamide was removed by vacuum distillation, the residue was dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a solid (0.063 g). .

m.p. 117-118 ℃

MS (APCI) 431 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.47 (1 H, dd); 7.55-7.48 (5H, m); 7.29-7. 26 (1 H, m); 7.25-7.20 (2H, m); 6.96 (2H, doublet); 5.50 (1 H, br.s); 4.41-4.37 (1 H, m); 3.90-3.80 (1 H, m); 3.57 (2H, s); 3.05-2.90 (1 H, m); 2.80-2.65 (2H, m); 2.18 (1 H, d); 1.90-1.80 (2H, m); 1.30 (3 H, d); 0.75-0.70 (2H, m); 0.45-0.40 (2H, m).

Example 68

(1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-yl] -1-pyrrolidin-1-yl Ethanon.

Prepared according to the method described in Example 66. (1S, 2R)-[4 ′-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetic acid (Example 55, 0.07 g ), Pyrrolidine (0.014 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were converted into dimethylformamide ( 2 ml) and stirred at room temperature for 16 hours. Dimethylformamide was removed by vacuum distillation and the residue was dissolved in dichloromethane, filtered and purified by standard HPLC, eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as glass ( 0.068 g).

MS (APCI) 435 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1H, doublet); 7.55 (1 H, dt); 7.50-7.47 (4H, m); 7.32 (2H, d); 7.24-7. 22 (1 H, m); 6.95-6.92 (2H, m); 4.40-4.36 (1 H, m); 3.87-3.86 ((1H, m); 3.68 (2H, s); 3.53-3.44 (4H, m); 3.0-2.90 (1H, m); 2.80-2.65 (1H, m); 2.15 (1H, d) 2.0-1.80 (6H, m); 1.30 (3H, d).

Example 69

(1S, 2R) -2-Methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulphonic acid amide.

a) 3-bromo-4-methylphenylsulphonic acid amide

A solution of 3-bromo-4-methylaniline (3.0 g) in concentrated hydrochloric acid (15 ml) was cooled to below 5 ° C. A solution of sodium nitrite (1.17 g) dissolved in water (4 ml) was added dropwise while keeping the internal temperature below 5 ° C. After the addition was completed, anhydrous magnesium chloride (2.0 g) was added (note the exotherm). A saturated sulfur dioxide solution in glacial acetic acid (40 ml) was prepared at 0 ° C. and cupric (II) chloride (0.22 g) was added. A solution of diazonium salt was added to this acetic acid solution at room temperature and the mixture was warmed up to 30 ° C. After 1 h, the mixture was poured into saturated brine and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residual oil was dissolved in tetrahydrofuran (50 ml) and ammonium hydroxide (50 ml) was added. After 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate: isohexane (1: 1) to give the subtitle compound as a solid (0.49 g).

MS (APCI-ve) 249/251 (MH) ^-

¹ H NMR (CDCl ₃ ) 8.09 (1 H, s); 7.76 (1 H, d); 7.38 (1 H, d); 4.85 (2H, br.s); 2.48 (3H, s).

b) (1S, 2R) -2-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulphonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, Example 33), 3-bromo-4-methylphenylsul Phonic acid amide (0.25 g, Example 69a), ethanol (3 ml), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) were heated at 90 ° C. for 2 hours. Prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give the title compound as a foam (0.19 g).

MS (APCI) 427 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.48 (1 H, s); 8.44 (1 H, d); 7.78 (1 H, s); 7.77 (1 H, d); 7.57 (1 H, d); 7.39 (1 H, d); 7.25 (1 H, d); 7.21 (2H, d); 6.93 (2H, d); 5.00 (2H, br.s); 4.40 (1 H, m); 3.87 (1 H, m); 2.95 (1 H, m); 2.75 (1 H, m); 2.33 (3H, s); 1.85 (2H, m); 1.33 (3 H, d).

Example 70

(1S, 2R) -2,2,2, -Trifluoro-N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3- General] -N-methylacetamide.

a) N- (3-bromo-phenyl) -2,2,2-trifluoro-N-methylacetamide

N- (3-bromophenyl) -2,2,2-trifluoroacetamide (J. Chem. Soc., 1952, 4014) in tetrahydrofuran (3 ml) was dissolved in tetrahydrofuran (5 ml) Dropwise to the lead (0.16 g). The reaction mixture was stirred at room temperature for 30 minutes. Iodomethane (0.25 ml) was added dropwise to the reaction mixture and stirred overnight at room temperature. Water was added and the product extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with isohexane: dichloromethane (1: 1) to give a subtitle compound as an oil (0.385 g).

¹ H NMR (CDCl ₃ ) 7.57 (1H, d); 7.43 (1 H, s); 7.32 (1 H, t); 7.21 (1 H, d); 3.35 (3H, s).

b) (1S, 2R) -2,2,2-Trifluoro-N- [4 '(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3- General] -N-methylacetamide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), N- (3-bromo-phenyl ) -2,2,2-trifluoro-N-methylacetamide (0.282 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in ethanol (3 ml) Was prepared according to the method described in Example 12b by heating at 90 ° C. for 2 hours. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane. The obtained product was dissolved in dichloromethane (3 ml) and cooled to 0 ° C. Trifluoroacetic anhydride (0.09 ml) was added dropwise and the reaction mixture was stirred at rt for 1 h and concentrated under reduced pressure. Methanol (10 ml) and water (10 ml) were added and the resulting mixture was stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil (0.148 g).

MS (APCI) 459 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.82 (1 H, s); 8.65 (1 H, d); 8.18 (1 H, d); 7.74 (1 H, t); 7.57 (1 H, d); 7.52-7.45 (3H, m); 7.40 (1 H, s); 7.18 (1 H, d); 6.97 (2H, d); 5.10 (1 H, br. S); 4.42-4.36 (1 H, m); 3.84-3.79 ((1H, m); 3.40 (3H, s); 3.18-3.10 (1H, m); 3.02-2.94 (1H, m); 1.96-1.90 (2H, m); 1.31 (3H, d) .

Example 71

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3,4-dicarbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.197 g, Example 33), 4-iodo-1,2- From dicyanobenzene (0.421 g, Can. J. Chem. 1985, 63, 3057), 2M aqueous sodium carbonate solution (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.054 g) in ethanol (3 ml) Prepared according to the method described in Example 12b. The reaction mixture was heated at 90 ° C. for 4 hours in a sealed vial. After cooling, the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate. The residue was further purified by silica gel chromatography eluting with dichloromethane: 2-propanol (19: 1). The residue was then further purified by reverse phase HPLC eluting with a 25-100% acetonitrile gradient in 0.1 w / v ammonium acetate aqueous solution. The HPLC fractions were concentrated under reduced pressure, and the residue was dissolved in dichloromethane, filtered and concentrated under reduced pressure. The residue was triturated with ether to give the title compound as a solid (0.060 g).

m.p. 135.5-137 ℃

MS (APCI) 384 (M + H) ⁺

¹ H NMR (DMSO) 8.47-8.43 (2H, m); 8.38 (1 H, dd); 8.25-8.12 (2H, m); 7.79 (2H, d); 7.63 (1 H, dt); 7.30 (1 H, dd); 7.06 (2H, d); 5.03 (1 H, d); 4.41 (1H, quintet); 3.63-3.5 ((1H, m); 2.9-2.75 (1H, m); 2.75-2.6 (1H, m); 1.95-1.8 (1H, m); 1.75-1.55 (1H, m); 1.24 (3H, d).

Example 72

(3R, 4S) -1-pyridin-3-yl-4- [3 '-(pyrrolidine-1-sulfonyl) biphenyl-4-yloxy] pentan-3-ol.

a) 3-bromobenzenesulfonic acid, pyrrolidinyl amide.

A solution of triethylamine (0.6 ml) in pyrrolidine (0.33 ml) and dichloromethane (10 ml) was added dropwise to a stirred solution of 3-bromobenzenesulfonyl chloride (1 g) in dichloromethane (20 ml), and the mixture was Stir at room temperature for 18 hours. The reaction was poured into water and the aqueous mixture was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This was purified by silica gel column chromatography eluting with ethyl acetate: isohexane (1: 4) to give a subtitle compound as a solid (1.10 g).

m.p. 82-84 ℃

MS (APCI) 290 (M + H) ⁺

¹ H NMR (DMSO) 7.95-7.9 (2H, m); 7.85-7.8 (1 H, m); 7.60 (1 H, t); 3.2-3.13 (4H, m); 1.75-1.6 (4H, m).

b) (3R, 4S) -1-pyridin-3-yl-4- [3 '-(pyrrolidine-1-sulfonyl) biphenyl-4-yloxy] pentan-3-ol.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.150 g, Example 33), 3-bromobenzenesulfonic acid, Prepared according to the method described in Example 12b from pyrrolidinyl amide (0.290 g), 2M aqueous sodium carbonate solution (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (3 ml). . The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give a gum which was further purified by reverse phase HPLC to give the title compound as a foam. Was obtained (0.137 g).

MS (APCI) 467 (M + H) ⁺

¹ H NMR (DMSO) 8.44 (1 H, s); 8.38 (1 H, d); 7.95-7. 88 (2H, m); 7.75-7.6 (5 H, m); 7.30 (1 H, q); 7.4 (2H, d); 5.01 (1 H, d); 4.4-4.3 (1 H, m); 3.6-3.5 (1 H, m); 3.18 (4H, t); 2.9-2.6 (2H, br.m); 1.92-1.8 (1 H, m); 1.7-1.6 (5H, m); 1.25 (3 H, d).

Example 73

(1S, 2R) -6-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carbonitrile

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g, Example 33), 3- Bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate solution (0.76 ml) and tetrakis (triphenylphosphine) palladium (0) (0.019 g) in ethanol (5 ml) for 4 hours at 90 ° C. By heating, it was prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as an oil (0.22 g).

MS (APCI) 377 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, d); 8.46 (1H, doublet); 7.73 (1 H, doublet); 7.62-7.54 (2H, m); 7.45 (2H, doublet); 7.43-7.22 (2H, m); 6.97 (2H, d); 4.42-4.39 (1 H, m); 3.87-3.86 (1 H, m); 2.96-2.94 (1 H, m); 2.76-2.72 (1 H, m); 2.21 (1 H, d); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 74

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-3-sulphonic acid amide

a) 3-bromo-5-trifluoromethylbenzenesulfonamide

3-Amino-5-bromobenzotrifluoride was added to concentrated hydrochloric acid (20 ml) and cooled to -5 ° C. A saturated solution of sodium nitrite (3.88 g) in water (4 ml) was added dropwise at a rate that kept the temperature below 0 ° C. Magnesium chloride (8 g) was added (note the exotherm) and the resulting mixture was added with stirring to saturated sulfur dioxide in acetic acid (37.5 ml) and toluene (20 ml) containing cupric chloride (2.75 g) at room temperature. The mixture was stirred for 16 hours, poured into water and extracted with toluene. The combined toluene extracts were washed with water, diluted with sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (200 ml) and 880 ammonia (50 ml) was added to this solution. The mixture was stirred at rt for 4 h and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated to give the subtitle compound as a solid (4.2 g).

m.p. 174-175 ℃

MS (APCI) 302/304 (MH ⁺ )

¹ H NMR (CDCl ₃ ) 8.31 (1H, s); 8.27 (1 H, s); 8.11 (1 H, s); 7.72 (2H, s).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-3-sulphonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33), 3-bromo-5-trifluoro From chloromethylbenzosulfonamide (0.40 g, Example 74), 2M aqueous sodium carbonate solution (0.76 ml) and tetrakis (triphenylphosphine) palladium (0) (0.019 g) in ethanol (5 ml) at 90 ° C. for 4 hours. Thus, it was prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a solid (0.24 g).

m.p. 57-59 ℃

MS (APCI) 481 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.49 (1 H, d); 8.45 (1 H, dd); 8.26 (1 H, s); 8.09 (1 H, s); 7.95 (1 H, s); 7.59-7.56 (1 H, m); 7.54 (2H, d); 7.26-7. 22 (1 H, m); 6.98 (2H, d); 5.18 (1 H, br. S); 4.42-4.39 (1 H, m); 3.87-3.84 (1 H, m); 2.95-2.93 (1 H, m); 2.77-2.73 (1 H, m); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 76

(1S, 2R) -N- [3-Fluoro-4 '(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide.

a) 2-fluoro-4-iodo-acetanilide

2-fluoro-4-iodoaniline (5.0 g) was heated at reflux in acetic anhydride (50 ml). The reaction was terminated by pouring into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by silica gel flash chromatography eluting with isohexane: ethyl acetate (4: 1) to give a subtitle compound as a solid (0.390 g).

m.p. 155-156 ℃

MS (GCMS) 279 (M) ⁺

¹ H NMR (CDCl ₃ ) 9.78 (1 H, br.s); 7.73 (1 H, t); 7.65 (1 H, m); 7.50 (1 H, bd); 2.08 (3H, s).

b) (1S, 2R) -N- [3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acet amides.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.200 g, Example 33), 2-fluoro-4-iodo -Heated at 90 ° C. for 4 hours from acetanilide (0.279 g, Example 76a), ethanol (3 ml), 2M aqueous sodium carbonate solution (0.67 ml) and tetrakis (triphenylphosphine) palladium (0) (0.030 g), Prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to give the title compound as a foam (0.107 g).

MS APCI 409 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, m); 8.45 (1 H, m); 8.32 (1 H, t); 7.56 (2H, m); 7.45 (2 H, m); 7.20-7.32 (3H, m); 6.93 (2H, d); 4.38 (1 H, m); 3.86 (1 H, bm); 2.95 (1 H, m); 2.73 (1 H, m); 2.35 (1 H, br. S); 2.39 (3H, s); 1.85 (2H, m); 1.31 (3 H, d).

Example 77

(1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -6-methyl-biphenyl-3-carboxylic acid methylamide.

a) 3-bromo-4-methylbenzoic acid, methyl amide.

Oxylyl chloride (1.45 ml) was added dropwise to a stirred solution of 3-bromo-4-methylbenzoic acid (3.5 g) in dichloromethane (25 ml) and dimethylformamide (1 drop). This mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in tetrahydrofuran (10 ml). A portion of this solution (5 ml) was added dropwise to a methylamine stirred solution in tetrahydrofuran (2M, 10 ml) and stirred for 3 days at room temperature. The mixture was poured into water and the organic layer was separated. The organic layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with ethyl acetate: isohexane (3: 1) to give the subtitle compound as a solid (1.33 g).

m.p. 114-116 ℃

MS (APCI) 228/230 (M + H) ⁺

¹ H NMR (DMSO) 8.5 (1 H, br d); 8.03 (1H, d); 7.74 (1 H, dd)); 7.44 (1 H, d); 2.77 (3H, d); 2.52-2.48 (3H, m).

b) (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -6-methylbiphenyl-3-carboxylic acid methylamide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33), 3-bromo-4-methylbenzo Prepared according to the method described in Example 12b from Ichacid, methyl amide (0.30 g), 2M aqueous sodium carbonate solution (0.66 ml) and tetrakis (triphenylphosphine) palladium (0) (0.038 g) in ethanol (3 ml). . The reaction mixture was heated at 90 ° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane and filtered and purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to give an oil which was eluted with ethyl acetate: ethanol (9: 1). Further purification by silica gel column chromatography gave the title compound as a foam (0.20 g).

MS APCI 405 (M + H) ⁺

¹ H NMR (DMSO) 8.40 (3H, m); 7.73-7.6 (3 H, m); 7.39-7. 25 (4H, m); 6.98 (2H, d); 5.00 (1H, d); 4.33 (1 H, t); 3.56 (1 H, d); 2.87-2.6 (5H, m); 2.27 (3H, s); 1.95-1.82 (1 H, m); 1.7-1.6 (1 H, m); 1.25 (3 H, d).

Example 78

(1S, 2R) -4-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide.

a) 5-bromo-2-methylaniline

Slurry of 5-bromo-2-methylnitrobenzene (3.00 g), iron powder (3.11 g) and ammonium chloride (2.97 g) in ethanol: water (3: 1) (50 ml) at reflux for 1 hour Heated. The mixture is poured into 10% aqueous sodium hydroxide solution and Celite Filtered through. The filtrate was extracted with ethyl acetate, the extract was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the subtitle compound as an oil (2.64 g).

¹ H NMR (CDCl ₃ ) 6.89 (1 H, d); 6.79 (2H, m); 3.64 (2H, broad singlet); 2.10 (3H, s).

b) 5-bromo-2-methylbenzenesulfonic acid amide

Acetic acid and copper chloride saturated with 5-bromo-2-methylaniline (2.60 g, Example 78a), sodium nitrite (1.05 g), concentrated hydrochloric acid (20 ml), magnesium chloride anhydride (2.6 g), sulfur dioxide (50 ml) (II) (0.37 g) was prepared by the method of Example 69a. Conventional reaction finishing followed by ammonium hydroxide (50 ml) treatment and other similar reaction finishing yielded a subtitle compound as a solid (0.42 g).

MS (APCI) 248/250 (MH) ⁺

¹ H NMR (CDCl ₃ ) 8.15 (1 H, s); 7.58 (1 H, d); 7.20 (1 H, d); 4.86 (2H, br. S); 2.63 (3H, s).

c) (1S, 2R) -4-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.2 g, Example 33), 5-bromo-2-methylbenzene Heated at 80 ° C. for 3 hours from sulfonic acid amide (1.7 g, Example 78a), ethanol (3 ml), 2M aqueous sodium carbonate solution (0.7 ml), and tetrakis (triphenylphosphine) palladium (0) (0.03 g) Thus, it was prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a foam (0.10 g).

MS APCI 427 (M + H) ⁺

NMR (CDCl ₃ ) 8.50 (1 H, s); 8.45 (1 H, d); 8.20 (1 H, s); 7.63 (1 H, d); 7.56 (1 H, d); 7.50 (2H, d); 7.37 (1 H, d); 7.24-7. 21 (1 H, m); 6.95 (2H, d); 4.95 (2H, s); 4.42-4.38 (1 H, m); 3.87 (1 H, br. S); 2.98-2.91 (1 H, m); 2.77-2.71 (4H, m); 2.26 (1 H, br. S); 1.94-1.79 (2H, m); 1.31 (3 H, d).

Example 79

(1S, 2R) -3-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide.

a) 4-bromo-2-methylbenzenesulfonic acid amide

Acetic acid and copper chloride saturated with 3-bromo-4-methylaniline (2.60 g, Example 78a), sodium nitrite (1.05 g), concentrated hydrochloric acid (20 ml), magnesium chloride anhydride (2.6 g), sulfur dioxide (50 ml) Prepared by the method of Example 69a using (II) (0.37 g). Conventional reaction finishing followed by treatment with ammonium hydroxide (50 ml) followed by the same reaction finishing yielded a subtitle compound as a solid (1.51 g).

m.p. 179-180 ℃

MS (APCI) 250/251 (MH ⁺ )

¹ H NMR (CDCl ₃ ) 7.76 (1H, d); 7.64 (1 H, s); 7.59 (1 H, d); 7.49 (2H, br. S); 2.57 (3H, s).

b) (1S, 2R) -3-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.2 g, Example 33), 4-bromo-2-methylbenzene From sulfonic acid amide (1.7 g, Example 79a), ethanol (3 ml), 2M aqueous sodium carbonate solution (0.7 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) at 80 ° C. for 3 hours , According to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a foam (0.13 g).

MS (APCI) 427 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, s); 8.46 (1 H, d); 8.05 (1H, d); 7.57-7.46 (5H, m); 7.26-7.21 (1 H, m); 6.97 (2H, d); 4.83 (2H, s); 4.42-4.39 (1 H, m); 3.92-3.83 (1 H, m); 3.01-2.91 (1 H, m); 2.79-2.69 (4H, m); 2.17-2.14 (1 H, m); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 80

(1S, 2R) -3-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide.

b) (1S, 2R) -3-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide.

4-[(2S, 3R) -5- (pyridin-3-yl) -3-hydroxypent-2-yloxy] benzeneboronic acid (0.20 g, Example 33), 4-bromo-2 From fluorophenylsulphonic acid amide (0.20 g), ethanol (3 ml), 2M aqueous sodium carbonate solution (1.0 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) at 90 ° C. for 3 hours. , According to the method described in Example 12b. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane and then recrystallized from aqueous ethanol solution to give the title compound as a solid (0.11 g).

m.p. 178.5-179.5 ℃

MS (APCI) 431 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.44 (1 H, s); 8.39 (1 H, d); 7.80 (1 H, dd); 7.65 (7 H, m); 7.30 (1 H, dd); 7.03 (2H, d); 5.01 (1 H, d); 4.37 (1 H, m); 3.55 (1 H, m); 2.80 (1 H, m); 2.65 (1 H, m); 1.84 (1 H, m); 1.64 (1 H, m); 1.24 (3 H, d).

Example 81

(1S, 2R) -3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-carbonitrile.

(1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-fluoro Heated at 90 ° C. for 4 hours from tetrakis (triphenylphosphine) palladium (0) (0.03 g) in benzonitrile (0.16 g), 2M aqueous sodium carbonate solution (0.76 ml) and ethanol (3 ml), described in Example 12b. It was prepared according to the method described. After completion of the reaction, the residue was purified by standard phase HPLC eluting with a 0-25% ethanol gradient in dichloromethane to afford the title compound as a gum (0.14 g).

MS (APCI) 377/378 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, s); 8.46 (1 H, d); 7.64 (1 H, dd); 7.24 (1H, doublet); 7.52 (3H, m); 7.43 (1 H, dd); 7.37 (1 H, dd); 6.98 (2H, d); 4.41 (1 H, m); 3.85 (1 H, m); 2.96 (1 H, m); 2.75 (1 H, m); 2.25 (1 H, br. S); 1.87 (2H, m); 1.32 (3H, d).

Example 82

(1S, 2R) -3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid amide, hydrochloride.

a) 2-fluoro-5-bromobenzamide

5-Bromo-2-fluorobenzonitrile (0.370 g) was heated at 110 ° C. for 1 h in concentrated sulfuric acid (10 ml). After cooling, the reaction solution was diluted with cooling water, and the slurry was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and evaporated to give a subtitle compound as a solid (0.328 g).

¹ H NMR (CDCl ₃ ) 8.26 (1 H, m); 7.61 (1 H, m); 7.05 (1 H, m); 6.64 (1 H, bs); 5.89 (1H, broad singlet).

b) (2S, 3R) -2- (4'-Fluoro-3'carboxamide-4-biphenyloxy) -5- (pyridin-3-yl) -pentan-3-ol, hydrochloride.

(1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.200 g, Example 11), 5- At 60 ° C. from bromo-2-fluorobenzamide (0.158 g, Example 82a), ethanol (3 ml), 2 M aqueous sodium carbonate solution (0.48 ml) and tetrakis (triphenylphosphine) palladium (0) (0.30 g) Prepared according to the method described in Example 12b by heating for 8 hours. After cooling, the reaction mixture was evaporated and azeotropic with ethanol. The residue was taken up in acetone, filtered through a pad of silica gel and evaporated to give an oil, which was stirred for 1 h in a mixture of methanol (4 ml) and concentrated hydrochloric acid (1 ml) at room temperature. The reaction was cooled in an ice bath, diluted with water and basified to pH 9 by the careful addition of sodium bicarbonate solution. The product was extracted with ethyl acetate and the organic layers combined and dried over magnesium sulfate anhydride, filtered and evaporated. The residue was purified by standard phase HPLC eluting with a 0-10% ethanol gradient in dichloromethane to afford the title compound as a foam (0.040 g).

MS (APCI) 395 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, s); 8.46 (1 H, m); 8.30 (1 H, m); 7.66 (1 H, m); 7.56 (1 H, m); 7.50 (2H, d); 7.20 (2 H, m); 6.97 (2H, d); 6.74 (1 H, br.m); 5.98 (1 H, br. S); 4.39 (1 H, m); 3.87 (1 H, m); 2.96 (1 H, m); 2.74 (1 H, m); 2.44 (1 H, br. S); 2.17 (1 H, s); 1.84 (2H, m); 1.31 (3 H, d).

Example 85

(1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N-methylpropionamide.

a) (2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naph-2-yl] propenoic acid, methyl ester .

(2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pent-3-ol (0.68 g, Example 10), methyl acrylate (0.76 g) Prepared according to the method described in Example 40a from a solution in acetonitrile (10 ml) of palladium acetate (0.04 g), tri-o-tolylphosphine (0.11 g) and triethylamine (2 ml). After completion of the reaction, the crude product was purified by silica flash column chromatography eluting with 20% acetone in isohexane and then 50% acetone in isohexane to give the subtitle compound as an oil (0.73 g).

MS (APCI) 392 (M + H) ⁺

NMR (CDCl ₃ ) 8.52 (1H, d); 8.46 (1H, doublet); 7.85 (1 H, s); 7.79 (1 H, d); 7.73 (1 H, d); 7.64 (1 H, dd); 7.61 (1 H, dd); 7.56 (1 H, d); 7.24-7.20 (1 H, m); 7.16 (1 H, dd); 7.12 (1 H, dd); 6.52 (1H, d); 4.53-4.50 (1 H, m); 3.94-3. 88 (1 H, m); 3.83 (3 H, s); 2.99-2.92 (1 H, m); 2.81-2.73 (1 H, m); 2.18 (1 H, br. S); 1.92-1.85 (2H, m); 1.36 (3 H, d).

b) (2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naph-2-yl] propanoic acid, methyl ester .

(2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naph-2-yl] propenoic acid, methyl ester (0.73 g, Example 84b), 10% palladium on carbon (0.2 g) and ethanol (50 ml) were prepared according to the method described in Example 40b. After completion of the reaction, the crude product was purified by silica flash column chromatography eluting with 5% ethanol in dichloromethane to give an oil (0.57 g).

MS (APCI) 394 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.52 (1H, s); 8.46 (1 H, d); 7.69 (1 H, d); 7.63 (1 H, d); 7.56 (2H, doublet); 7.30 (1 H, d); 7.24-7. 21 (1 H, m); 7.10 (2H, d); 4.49-4.48 (1 H, m); 3.98-3.87 (1 H, m); 3.67 (3H, s); 3.08 (2H, t); 3.09-3.06 (1 H, m); 2.72-2.69 (3H, m); 1.80 (1 H, br. S); 1.89-1.85 (2H, m); 1.35 (3 H, d).

c) (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N-methyl-propionamide.

Trimethylammonium (2.0 M solution in toluene, 2.9 ml) was carefully added to a suspension of methylamine hydrochloride (0.39 g) in toluene (6 ml) with stirring at 0 ° C. under nitrogen. During the addition, the reaction temperature was maintained between 0 ° C and 5 ° C. The reaction mixture was then left to come to room temperature for about 1 hour. This aluminum / amide reactant was converted to (2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naphth-2 in toluene (20 ml). -Yl] propanoic acid, a solution of methyl ester (0.57 g, Example 84b) was added and heated at reflux for 16 h under nitrogen. After cooling, the reaction mixture was acidified with 2M hydrochloric acid and stirred for 1 hour. The aqueous layer was separated, basified by addition of saturated solution of sodium bicarbonate, and extracted with ethyl acetate (3 x 100 ml). The ethyl acetate fractions were combined, washed with brine and dried over magnesium sulfate anhydride. After filtration, the solvent was removed by evaporation under reduced pressure and the residue was purified by silica flash column chromatography eluting with 5% ethanol in dichloromethane to afford the title compound as a solid (0.2 g).

m.p. 68-70 ℃

MS (APCI) 393 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.51 (1H, s); 8.46 (1 H, d); 7.68 (1 H, d); 7.63 (1 H, d); 7.55 (2H, d); 7.30 (1 H, dd); 7.24-7.20 (1 H, m); 7.12-7.08 (2H, m); 5.32 (1 H, br.s); 4.50-4.47 (1 H, m); 3.91-3.88 (1 H, m); 3.10 (2H, t); 3.01-2.90 (1H, m); 2.85-2.70 (4H, m); 2.53 (2H, t); 2.21 (1 H, d); 1.90-1.84 (2H, m); 1.34 (3 H, d).

Example 86

3-cyano-4-fluorobenzeneboronic acid

n-butyllithium solution (2.5 M in hexane, 5.6 ml) was added to a solution of 5-bromo-2-fluorobenzonitrile and triisopropylborate (3.46 ml) in tetrahydrofuran (10 ml) at -78 ° C for 20 minutes Added over. The resulting solution was stirred at −78 ° C. for 30 minutes and then the reaction was terminated by addition of 2M hydrochloric acid (20 ml) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by triturate using diethyl ether: hexane (1: 2) to give the subtitle compound as a solid (1.24 g).

m.p.> 250 ° C

MS (APCI-ve) 164 (MH) ^-

¹ H NMR (DMSO / D ₂ O) 8.20 (1 H, dd); 8.16-8.12 (1 H, m); 7.53-7.49 (1 H, m).

Example 87

(1S, 2R) -4-fluoro-4 '-(1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile.

a) (2S) -2- (4-bromophenoxy) butanoic acid, methyl ester

Diethylazodicarboxylate (7.8g), 4-bromophenol (7.8g), triphenylphosphine (11.8g) and R-2-hydroxybutanoic acid, methyl ester (5.31g, Tetrahedron, 35 1601) from tetrahydrofuran anhydride was prepared according to the method described in Example 1a. After completion of the reaction, the crude material was purified by silica flash column chromatography eluting with 30% dichloromethane in isohexane to give a subtitle compound as an oil (7.53 g).

¹ H NMR (CDCl ₃ ) 7.37 (2H, dt); 6.76 (2H, dt); 4.52 (1 H, t); 3.75 (3 H, s); 2.03-1.94 (2H, m); 1.07 (3 H, t).

b) (2S) -2- (4-bromophenoxy) -1-butanol

(2S) -2- (4-Bromophenoxy) butanoic acid, methyl ester (7.53 g, Example 87a) and sodium borohydride (1.09 g) in a solution in ethanol (100 ml) described in Example 4b It was prepared according to the method described. After completion of the reaction, the crude material was purified by silica flash column chromatography eluting with dichloromethane to give a subtitle compound as an oil (5.24 g).

¹ H NMR (CDCl ₃ ) 7.37 (2H, dt); 6.83 (2H, dt); 4.28-4.21 (1 H, m); 3.85-3.70 (2H, m); 1.85-1.81 (1 H, m); 1.77-1.57 (2H, m); 0.96 (3H, t).

c) (3RS, 4S) -4- (4-bromophenoxy) -1-pyridin-3-yl-hex-1-yn-3-ol

Freshly activated (dried in a 300 ° C. oven) powdered molecular sieves (20 g, 3 μs, <5 microns) were converted to (2S) -2- (4-bromophenoxy) -1-butanol (5.24 g, Example 87b) and pyridinium dichromate (12.07 g) were added to a solution in anhydrous dichloromethane (200 ml). The mixture was treated with acetic anhydride (2 drops) and stirred under nitrogen for 2 hours. Celite (10 g) was added to this reaction mixture and it was stirred for 20 minutes. Isohexane (100 ml) was added thereto and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue obtained was triturated with diethyl ether. It was filtered through anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure. The obtained residue was estimated to be (2S) -2- (4-bromophenoxy) -1-butanal, which was dissolved in anhydrous tetrahydrofuran (40 ml). n-butyl-lithium (5.88 ml, 2.5 M solution in hexane) was added anhydrous tetrahydrofuran (80 ml) solution of pyridin-3-ylacetylene (1.6 g, J. Amer. Chem. Soc. 1935, 57, 1284) Was added dropwise under nitrogen at −70 ° C. After stirring for 20 minutes, (2S) -2- (4-bromophenoxy) -1-butanal solution in tetrahydrofuran was added dropwise while maintaining the reaction temperature at -70 ° C. The reaction mixture was then slowly warmed to 0 ° C. and poured into brine (200 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic fractions were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an oil which was purified by silica flash column chromatography eluting with isohexane: ethyl acetate (2: 1). This resulted in the subtitle compound as an oil (3.42 g).

MS (APCI) 348 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.70 (1H, dd); 8.51 (1 H, dd); 7.69-7.65 (1 H, m); 7.40-7.36 (2H, m); 7.27-7.23 (1 H, m); 6.93-6.88 (2H, m); 4.81 (1 H, t); 4.37-4.33 (1 H, m); 3.24 (1 H, d); 1.94-1.89 (2H, m); 1.08-1.01 (3H, m).

d) (3R, 4S) -4- (4-bromophenoxy) -1-pyridin-3-yl-hexan-3-ol

(3RS, 4S) -4- (4-Bromophenoxy) -1-pyridin-3-yl-hex-1-yn-3-ol (3.42 g, Example 87c) and carbon (0.5 g) Prepared according to the method described in example 1d from a solution in% rhodium in ethyl acetate (100 ml). After completion of the reaction, the crude material was purified by silica flash column chromatography eluting with ethyl acetate to give a mixture of diastereomers. This mixture was separated by standard phase HPLC eluting with 2% propan-2-ol in dichloromethane to give the subtitle compound as the second eluting major diastereoisomer (2 g).

MS (APCI) 350 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.48 (1 H, s); 8.45 (1 H, d); 7.52 (1 H, dt); 7.38-7. 34 (2H, m); 7.23-7.20 (1 H, m); 6.82-6.77 (2H, m); 4.15-4.10 (1 H, m); 3.83 (1 H, br. S); 2.96-2.89 (1 H, m); 2.73-2.66 (1 H, m); 2.08 (1 H, br. S); 1.89-1.61 (4H, m); 0.95 (3H, t).

e) (1S, 2R) -4-fluoro-4 '-(1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile.

(3R, 4S) -4- (4-Bromophenoxy) -1-pyridin-3-yl-hexan-3-ol (0.3 g, Example 87d), 3-cyano-4-fluorobenzene From tronic acid (0.17 g, Example 86), ethanol (3.0 ml), 2M sodium carbonate solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) at 100 ° C. for 4 h. Thus, it was prepared according to the method described in Example 12b. After completion of the reaction, the residue was purified by silica flash column chromatography eluting with isohexane: acetone (2: 1) to afford the title compound as an oil (0.17 g).

MS (APCI) 391 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.50 (1 H, s); 8.46 (1 H, d); 7.75-7.70 (2H, m); 7.57 (1 H, d); 7.42 (2H, d); 7.28-7.21 (2H, m); 7.00 (2H, d); 4.27-4.23 (1 H, m); 3.89-3.85 (1 H, m); 2.98-2.91 (1 H, m); 2.76-2.68 (1 H, m); 2.05 (1 H, br. S); 1.91-1.67 (4H, m); 0.99 (3H, t).

Example 88

(1S, 2R) -4 '-[1-ethyl-2-hydroxy-4-pyridin-3-yl-butoxy] -4-fluorobiphenyl-3-sulphonic acid amide.

a) (3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine.

Anhydrous N, N-dimethylformamide (30 ml) of (3R, 4S) -4- (4-bromophenoxy) -1-pyridin-3-yl-hexan-3-ol (1.34 g, Example 87d) To the solution tert-butyldimethylsilyl chloride (0.80 g) and imidazole (0.77 g) were added and the resulting solution was heated at 50 ° C. for 20 hours. This solution was concentrated in vacuo. The residue was basified by addition of saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with ethyl acetate: isohexane (1: 1) to give a subtitle compound as an oil (0.71 g).

MS (APCI) 466 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.43 (1H, dd); 8.40 (1 H, d); 7.41-7.33 (1 H, m); 7.34 (2H, d); 7.20-7.16 (1 H, m); 6.76 (2H, d); 4.11-4.08 (1 H, m); 3.92-3.90 (1 H, m); 2.88-2.78 (2H, m); 1.98-1.71 (4H, m); 0.96 (3H, t); 0.91 (9H, s); 0.06 (6H, d).

b) (1S, 2R) -4- [2- (t-butyldimethylsilanyloxy) -1-ethyl-4-pyridin-3-yl-butoxy] benzeneboronic acid.

(3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine (0.71 g, Example 88a), tertbutyl lithium (1.80 ml, 1.7 M in hexane) and tri-isopropylborate (0.74 ml) in solution in anhydrous tetrahydrofuran (25 ml) were prepared according to the method described in Example 5b. After completion of the reaction, the residue was purified by column chromatography eluting with a 0-25% ethanol gradient in ethyl acetate to give the subtitle compound as a foam (0.41 g).

MS (APCI) 430 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.53-8.51 (2H, m); 7.95 (2H, d); 7.45-7.42 (1 H, m); 7.22-7.18 (1 H, m); 6.89 (2H, d); 4.20-4.16 (1 H, m); 3.98-3. 93 (1 H, m); 3.76-3.69 (1 H, m); 2.74-2.61 (2H, m); 1.98-1.91 (1 H, m); 1.82-1.73 (3H, m); 1.60 (1 H, br. S); 0.98 (3H, t); 0.92 (9H, s); 0.02 (6H, d).

c) (1S, 2R) -4 '-[1-ethyl-2-hydroxy-4-pyridin-3-yl-butoxy] -4-fluorobiphenyl-3-sulphonic acid amide.

(3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine (0.20 g, Example 88b), 2-fluoro-5- Bromophenylsulfonamide (0.177 g, Example 35a), 2M aqueous sodium carbonate solution (0.54 ml) and tetrakis (triphenylphosphine) palladium (0) (0.014 g) in ethanol (3 ml) for 4 hours at 90 ° C. Prepared according to the method described in Example 12b by heating. The residue was purified by silica column chromatography eluting with ethyl acetate to give the title compound as a foam (0.14 g).

MS (APCI) 445 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.49 (1 H, d); 8.45 (1 H, dd); 8.05 (1 H, dt); 7.74-7.68 (1 H, m); 7.55-7.52 (1 H, m); 7.46 (2H, d); 7.30-7.21 (2H, m); 6.98 (2H, d); 5.08 (2H, s); 4.23-4.21 (1 H, m); 3.96-3.85 (1 H, m); 2.95-2.86 (1 H, m); 2.74-2.64 (1 H, m); 1.96 (1 H, d); 1.91-1.83 (4H, m); 0.98 (3H, t).

Example 89

(1S, 2R) -3-chloro-4 '-(1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-4-carbonitrile.

(1S, 2R) -4- [2- (tertbutyldimethylsilanyloxy) -1-ethyl-4-pyridin-3-yl-butoxy] benzeneboronic acid (0.18 g, Example 88b), 4 Bromo-2-chlorobenzonitrile (0.18 g), 2M aqueous sodium carbonate solution (0.48 ml) and tetrakis (triphenylphosphine) palladium (0) (0.12 g) in ethanol (3 ml) for 4 hours at 90 ° C. Prepared according to the method described in Example 12b by heating. The residue was purified by column chromatography eluting with a 50-100% ethyl acetate gradient in isohexane to give the title compound as a solid (0.125 g).

m.p. 99-100 ℃

MS (APCI) 407 (M + H) ⁺

¹ H NMR (CDCl ₃ ) 8.48 (1H, d); 8.45 (1 H, dd); 7.70-7.56 (2H, m); 7.56-7.48 (2H, m); 7.51 (2H, d); 7.24-7.20 (1 H, m); 7.0 (2H, d); 4.27-4.25 (1 H, m); 3.86-3.80 (1 H, m); 2.94-2.92 (1 H, m); 2.74-2.69 (1 H, m); 2.12 (1 H, d); 1.92-1.73 (4H, m); 0.98 (3H, t).

Pharmacological activity

Methods, such as pharmacological activity of the wells (E. Wells) of the compounds of the invention [primate chevron nose albedo come mast cells Characterization of (primate bronchoalveolar mast cells) II: primate chevron nose albedo come histamine (LTC ₄ from mast cells and Inhibition of release of PGD ₂ ) and comparison with rat celiac mast cells, J. Immunol., Vol. 137, 3941, 1986].

The compounds of Examples 1-89 were assayed and found to inhibit histamine release at concentrations below ^10-5 M (IC ₅₀ ).

Claims (11)

A compound of formula (I) or a salt or solvate thereof. <Formula I> Where X is O or S; R ¹ and R ² are independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; R ³ is hydrogen and R ⁴ is C _1-6 alkyl or C _3-6 cycloalkyl, or R ³ and R ⁴ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; Ar ¹ is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl, wherein the four groups of naphthyl, phenyl, C _7-9 alkylphenyl or biphenyl are halo, nitro, Cyano, pyridyl, thiazinyl, C _1-10 alkyl (optionally substituted with one or more fluorine atoms), -Y-OR ⁵ , -Y-NR ⁶ C (O) NR ⁷ -R ⁸ , -OZC (O ) NR ⁷ R ⁸ , -OYC (S) NR ⁷ R ⁸ , -YC (O) NR ⁷ R ⁸ , -Y-SO ₂ NR ⁷ R ⁸ , -Y-NR ⁷ R ⁸ , -Y-OC (O ) NR ⁷ R ⁸ , -YC (S) NR ⁷ R ⁸ , -YC (O) R ⁹ , -Y-OC (O) R ⁹ , -Y-CO ₂ R ⁹ , -Y-NR ¹⁰ C (O ) NR ¹¹ -ZR ¹² , SO ₂ NR ¹⁰ C (O) NR ⁷ R ⁸ , -Y-SO ₂ NHNR ⁷ R ⁸ , -YC (O) NR ¹¹ -ZR ¹² , -YC (S) NR ¹¹ -ZR Optionally substituted with one or more groups selected from ¹² , -YN (R ¹⁰ ) SO ₂ R ¹¹ , -YN (R ¹⁰ ) C (O) R ^11, or -YN (R ¹⁰ ) CO ₂ R ¹¹ (wherein Y Is one bond, C _1-6 alkylene or C _2-6 alkenylene); R ⁷ and R ⁸ are independently hydrogen or C _1-6 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring, which heterocyclic ring is optionally Further contains a heteroatom selected from nitrogen, oxygen or sulfur; R ⁵ , R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ are independently hydrogen or C _1-10 alkyl optionally substituted with one or more fluorine atoms; Z is C _1-6 alkylene; R ¹² is NR ¹⁰ C (O) R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , OR ⁵ , NR ⁷ R ⁸ or CO ₂ R ¹³ , wherein R ⁵ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are As defined and R ¹³ is hydrogen, C _1-6 alkyl, C _1-6 alkylaryl or aryl optionally substituted with a hydroxy group. The compound of claim 1, wherein X is O. The compound of claim 1 or 2, wherein R ¹ and R ² are both hydrogen. The compound of any one of claims 1-3, wherein R ³ is hydrogen and R ⁴ is C _1-6 alkyl or R ³ together with R ⁴ form a cyclopropyl group. The compound of any one of claims 1-4, wherein Ar ¹ is naphthyl or biphenyl. The compound of claim 1, wherein Ar ¹ is biphenyl optionally substituted with one or more substituents selected from halo, cyano, methyl or SO ₂ NR ⁷ R ⁸ . The compound of claim 1, wherein (3R, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3S, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3S, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile, (1S, 2S) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -biphenyl-3-sulphonic acid amide, (1S, 2S) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -biphenyl-3-sulphonic acid amide, (3R, 4S) -4- (3'-chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3S, 4S) -4- (3'-chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (4′-Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3S, 4R) -4- (4'-Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-hexan-3-ol, (±) -1- [1- (biphenyl-4-yloxy) -cyclopropyl] -3-pyridin-3-yl-propan-1-ol, (2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol, (2R, 3S) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N-methylacetamide, (3R, 4S) -4- (4'-Chloro-2'-fluorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (4'-Chlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (5'-methoxy-2'-methylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (3 ', 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid (2-morpholin-4-ylethyl) amide , (3R, 4S) -4- (2 ', 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid methylamide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid (2-pyrrolidin-1-ylethyl) amides, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carbonitrile, (1S, 2R) -N- [2-Chloro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide, (3R, 4S) -4- (4'-Amino-2'-chloro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid (2-dimethylaminoethyl) amide, (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide, (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide, (3R, 4S) -4- [3 '-(2-dimethylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -2- [4 '(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -1-morpholin-4-yl-ethanone, (3R, 4S) -4- [4- (3 '-(methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- [4 '-(2-methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl-urea, (3R, 4S) -4- (3 ', 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid, (1S, 2R) -4 '(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -3-methyl-biphenyl-4-carbonitrile, (1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide, and (1S, 2S ) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide, (1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile, (1S, 2R) -2,5-difluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide, (1S, 2R) -3-chloro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-carbonitrile, (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N, N-dimethylacrylamide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-N-sulfonamido-N'-isopropyl urea, (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -1-morpholin-4-yl-propane -1-one, (3R, 4S) -4- [6- (3-Morpholin-4-yl-propyl) naphthalen-2-yloxy] -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- [6- (3-methylaminopropyl) naphthalen-2-yloxy] -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile, (3R, 4S) -1-pyridin-3-yl-4- [4 '-(2-pyrrolidin-1-yl-ethoxy) biphenyl-4-yloxy] pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -4- (2-morpholin-4-ylethoxy) biphenyl-3-carbonitrile , (3R, 4S) -4- (3'-methanesulfonylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carboxylic acid amide, (1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yloxy] acetamide, (2S, 3R) -1-pyridin-3-yl-4- (2'-trifluoromethoxybiphenyl-4-yloxy) pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -6-methoxybiphenyl-3-carbonitrile, (3R, 4S) -4- (4'-Chloro-2'-methoxy-5'-methylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid methylamide, (1S, 2R)-[4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] acetic acid, (1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-2-yl] acetamide , (1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-2-yl] -N-methylacetamide, (1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methylbiphenyl-4-yl] acetamide, (1S, 2R) -N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] -methanesulfonamide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide, (1S, 2R) -4 '-(2-hydroxy-1-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide, (1S, 2R)-[4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-yl] urea, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carboxylic acid (2-pyrrolidine -1-yl-ethyl) amide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid (2,2,2-trifluoroethyl) amides, (1S, 2R) -1- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -3-methyl urea, (1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -N-isopropylacetamide, (1S, 2R) -N-cyclopropyl-2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide, (1S, 2R) -2- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-yl] -1-pyrrolidin-1-yl Ethanol, (1S, 2R) -2-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulphonic acid amide, (1S, 2R) -2,2,2-Trifluoro-N- [4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-yl -]-N-methylacetamide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3,4-dicarbonitrile, (3R, 4S) -1-pyridin-3-yl-4- [3 '-(pyrrolidine-1-sulfonyl) biphenyl-4-yloxy] pentan-3-ol, (1S, 2R) -6-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carbonitrile, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-3-sulphonic acid amide, (1S, 2R) -N- [3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide, (1S, 2R) -4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -6-methyl-biphenyl-3-carboxylic acid methylamide, (1S, 2R) -4-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulphonic acid amide, (1S, 2R) -3-methyl-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulphonic acid amide, (1S, 2R) -3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-sulphonic acid amide, (1S, 2R) -3-Fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-carbonitrile, (1S, 2R) -4-fluoro-4 '-(2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid amide, (1S, 2R) -3- [6- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N-methyl-propionamide, (1S, 2R) -4-fluoro-4 '-(1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile, (1S, 2R) -4 '-[1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy] -4-fluorobiphenyl-3-sulphonic acid amide, (1S, 2R) -3-chloro-4 '-(1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-4-carbonitrile, (4S, 3R) -4- (4'-methanesulfonyl-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, Or salts or solvates thereof. A compound according to any one of claims 1 to 7 for use in therapy. A compound according to any one of claims 1 to 7 used for the treatment or prevention of asthma or rhinitis. A pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof as defined in any one of claims 1 to 7 together with a pharmaceutically acceptable adjuvant, diluent or carrier. (a) reducing the compound of formula II; or <Formula II> (Wherein R ³ , R ⁴ , X and Ar ¹ are as defined in formula (I).) (b) reducing the compound of formula III; or <Formula III> (Wherein R ¹ , R ² , R ³ , R ⁴ , X and Ar ¹ are as defined in formula (I).) (c) preparing a compound of formula I wherein Ar ¹ is a substituted biphenyl group by reaction of a compound of formula IV with a compound of formula V: <Formula IV> <Formula V> Wherein X, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula I, R ¹⁵ is an Ar ¹ substituent as defined in Formula I, R ¹⁶ is a suitable hydroxy protecting group, R One of ¹⁷ / R ¹⁸ is triflate or halo and the other is B (OH) ₂ or ZnHal.) Then, in any order, Removal of protector Converting One Compound Of Formula (I) To Another Compound Of Formula (I) To form pharmaceutically acceptable salts or solvates A process for preparing a compound of formula (I), comprising the process.